The congenital hearing phenotype in GJB2 in Queensland, Australia: V37I and mild hearing loss predominates

The congenital hearing phenotype in GJB2 in Queensland, Australia: V37I and mild hearing loss predominates | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The congenital hearing phenotype in GJB2 in Queensland, Australia: V37I and mild hearing loss predominates Karen Liddle, Rebecca Kriukelis, Michael Gabbett, Rachael Beswick, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3829481/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Guidelines recommend GJB2 (connexin 26) and GJB6 (connexin 30) testing for bilateral non-syndromic sensorineural hearing loss (SNHL). However, associated audiological phenotypes vary. There is limited Australian data on GJB2 variant frequency and associated phenotypes. Audiograms from a paediatric cohort with SNHL, predominantly identified through newborn hearing screening and carrying GJB2 variants and/or a GJB6 deletion ( GJB6 -D13S11830) were retrospectively reviewed (n = 127). Two thirds were homozygous or compound heterozygous for pathogenic or likely pathogenic variants of GJB2 and/or GJB6 (n = 80). The most frequent variant, c.109G > A, occurred in homozygous (n = 32), compound heterozygous (n = 8) and heterozygous (n = 5) states. Compared to homozygous/compound heterozygous carriage of other GJB2 variants, c.109G > A positive individuals (homozygous/compound heterozygous) were more likely to have mild HL at their initial (p = 0.00004) and latest audiograms (p = 0.0004). Homozygous/compound heterozygous carriage of c.35delG was associated with moderately-severe or greater HL at both initial (p = 0.007) and latest (p = 0.007) audiograms. The c.101T > C variant presented with milder HL and U-shaped audiograms (p = 0.02). In this agnostically identified cohort, mild HL predominated in GJB2/GJB6 carriers in contrast to previous studies targeting individuals with significant loss. Consequently, c.109G > A, associated with milder phenotypes, was the most frequent. This data provides valuable, balanced prognostic information for preconception, prenatal and paediatric counselling of couples and families carrying these variants. Health sciences/Medical research/Genetics research Health sciences/Health care/Paediatrics Biological sciences/Genetics/Clinical genetics/Genetic testing Biological sciences/Genetics/Medical genetics/Genetic counselling GJB2 GJB6 Connexin 26 Hearing loss genotype-phenotype paediatric deafness Figures Figure 1 INTRODUCTION Sensorineural hearing loss is the most common congenital sensory disorder, affecting 1 in 500 newborns [ 1 ]. It can adversely affect language development, cognition, psychosocial wellbeing and quality of life, educational attainment, and economic independence at various stages of life[ 2 ]. Approximately 50% of congenital hearing loss is Mendelian, with 30% of individuals having a recognised syndrome and 70% regarded as non-syndromic [ 3 ]. Non-syndromic hearing loss (NSHL) is heterogeneous with approximately 75% of early onset cases being inherited in an autosomal recessive manner [ 4 ]. Seventy-eight of the 124 NSHL genes are autosomal recessive [ 5 ], and the most frequently implicated gene is GJB2 (OMIM 121011), which is responsible for the protein gap junction protein beta-2 (connexin 26). However, a single GJB2 variant can lead to disease if coinherited with a variant in the contiguous gene GJB6 , (OMIM 604418) gap junction protein beta-6 (connexin 30) in approximately 2% of cases [ 5 , 6 ]. In addition, pathogenic variants in GJB2 can be associated with autosomal dominant inheritance in approximately 2% of cases [ 7 ]. Worldwide, GJB2 pathogenic variants account for 18%-50% of prelingual NSHL. [ 8 ] In addition, GJB2 variants account for 30–50% of all cases of profound NSHL [ 9 ]. Widespread testing of GJB2 (and GJB6 ), reveals variable degrees of hearing loss (mild to profound), not always detectable at birth, which is usually bilateral, but occasionally unilateral, and can be progressive [ 3 , 8 ]. Previous cohort studies identified a recurrent variant in GJB2 (c.35delG) estimated to account for approximately 60–70% of deafness in European, North African, Middle Eastern, Asian, North and South American populations [ 8 , 10 , 11 ]. A single study in an Australian paediatric population identified the c.35delG variant to be the most frequently implicated (38.03%) [ 12 ]. Other GJB2 variants have been implicated in other populations. Specifically, the c.235delC and c.109G > A GJB2 variants are more frequently implicated in hearing loss in East Asian countries including Japan, Korea and China [ 10 ]. There is significant genotypic and phenotypic variability in international studies, but limited data from Oceania. Of note, a recent systematic review identified that only 0.7% of publications about connexin gene variants were from Australia [ 11 ]. Thus, this study reviewed all GJB2 positive cases from the Queensland state laboratory, documented all GJB2 and GJB6 genotypes, and reviewed audiological and clinical data to identify possible genotype-phenotype correlations for a Queensland paediatric population with NSHL. METHODS Ethical Considerations This study was conducted in full conformance with principles of the ‘Declaration of Helsinki’ Good Clinical Practice and was approved by the Children’s Health Queensland Hospital and Health Service Human Research Ethics Committee (Protocol Number HREC/20/QCHQ/65404). Study population and context Queensland is an Australian state, where 99% of the 60 000 babies born each year, have newborn hearing screening as part of a state-government funded program (‘Healthy Hearing Program’). Screen positive individuals are referred for follow up diagnostic assessment in accordance with a state-wide protocol https://www.childrens.health.qld.gov.au/resources/our-work/healthy-hearing/queensland-health-screening-protocols-and-guidelines [ 13 ]. This study includes children diagnosed with a hearing impairment through this pathway or those diagnosed with hearing loss in later childhood (either through the targeted surveillance program or external referral). Included individuals were seen in specialised paediatric ENT and/or medical hearing loss clinics at Queensland Children’s Hospital and other public hospitals statewide who had subsequent genetic testing with Pathology Queensland. All individuals had undergone genetic testing between November 2014 and December 2019. Medical and audiological records of this paediatric population were retrospectively reviewed. Ancestral background information was not routinely available; however, recent census data shows that whilst English and Australian ancestry is more common (33.6% and 31.2% respectively), Chinese ancestry is the 5th most common in Australia (5.5% in the 2021 census), with a recent increase in the proportion of first-generation Chinese born people residing in Australia. Of note, First Nations peoples (Aboriginal and Torres Strait Islander peoples) were recorded at 3.2% of 2021 census [ 14 ]. Genetic Testing Pathology Queensland is a state-wide service offering genetic testing for individuals diagnosed with hearing loss. Specifically, the entire coding region of GJB2 is sequenced (Sanger sequencing) for all patients and no further testing is conducted on individuals found to carry biallelic variants. When GJB2 heterozygosity is identified, there is subsequent screening for a single GJB6 deletion (del( GJB6 -D13S11830) due to the interactive association. The study was confined to all patients that undertook GJB2 and GJB6 testing during the study period. Patients with no detected variants were excluded from the study. Medical records were reviewed for all cases including homozygous/compound heterozygous and heterozygous cases or a single GJB2 variant in the presence of a GJB6 deletion. Variant pathogenicity was initially evaluated by reviewing ClinVar [ 15 ] and the Deafness Variation Database [ 16 ] to determine prior association with disease. For all variants not reported in ClinVar, a Varsome assessment [ 17 ] rated their likely pathogenicity using the American College of Medical Genetics and Genomics guidelines and best practices for expert interpretation of genomic data [ 18 ]. Based on these categories individuals were classified as autosomal dominant pathogenic variant, homozygous for pathogenic variants, compound heterozygous for two pathogenic variants, compound heterozygous for two variants (at least one pathogenic), digenic (one GJB2 , one GJB6 ), heterozygous for pathogenic/likely pathogenic variants or heterozygous for VUS/likely benign/benign variant. The hearing profiles were included for all variant carriers, but statistical analyses (see below) were limited to individuals with biallelic pathogenic/likely pathogenic variants. Hearing assessment Information relating to the severity of hearing impairment and a description of the audiogram was collated. The sensorineural (permanent) component of the HL was used in the cases with mixed (both sensorineural and conductive) HL, and we aimed to exclude temporary conductive HL, but the distinction was not always apparent during early testing. Degrees of hearing loss were based on the classification system outlined by Goodman and Clark and include normal (≤ 20 dB HL), mild (21–40 dB HL), moderate (41–55 dB HL), moderately severe (56–70 dB HL), severe (71–90 dB HL), and profound (> 90 dB HL). A four-frequency average was used to determine the degree of hearing loss. [ 19 , 20 ] The audiograms were also assessed for shape (rising, sloping/descending, flat, U-shaped), symmetry (symmetrical, asymmetrical) and stability (fluctuating, progressive, stable). [ 21 , 22 ] (See Supplementary Table 1 for definitions of descriptors). If the hearing loss was asymmetrical, it was graded according to the better hearing side. Audiometric testing was performed using a variety of age-appropriate standardised techniques for paediatric populations https://www.childrens.health.qld.gov.au/resources/our-work/healthy-hearing/audiology-diagnostic-assessment-protocol [ 13 ]. In cases where consecutive reports were available, the stability of the hearing loss was also documented, by comparing audiogram results from the initial and most recent hearing assessment. Only patients with copies of audiograms in their medical record were included in the study. Audiology data was confirmed and supplemented through review of the QChild database, Queensland’s newborn hearing screening data management system which contains demographic and clinical information from screening. Data analysis All genetic and phenotypic data (extracted from patient medical records and QChild) were exported into Microsoft Excel. A descriptive statistical analysis was performed. Fisher exact statistical tests were used to determine whether specific genotypes were more frequently associated with milder or more severe audiological phenotypes as well as other audiological descriptors. Specific genotype-phenotype analysis was performed for individuals who had pathogenic or likely pathogenic variants that were inherited in a homozygous, compound heterozygous or autosomal dominant manner. Moderately-severe, severe and profound HL were grouped together due to sample size limitations. A p value < 0.05 was considered statistically significant. RESULTS Study Population Of the 625 individuals with GJB2 +/- GJB6 sequencing through Pathology Queensland during the study period (2014 to 2019), 134 had variants detected and sufficient audiological information. After review of patient medical records and QChild, seven patients had other known identifiable causes for their hearing impairment (three with absent cochlear nerves, two with enlarged vestibular aqueducts, one with Waardenburg syndrome and another with a chromosome 15q11.1 deletion) and were excluded. This left a total of 127 patients for analysis. Demographics The final 127 cohort consisted of 72 males and 55 females. The mean age at genetic testing was 1.8 years with the range between 2 months and 17 years. The median age of genetic testing was 4 months with 68% of the cohort having the testing under 12 months of age. Specific information about ancestral background was not consistently available. Genetic Findings: In the cohort of 127 patients, 36 different GJB2 variants were identified in a homozygous (n = 45/127, 35.4%), compound heterozygous (n = 36/127, 28.3%), 1 digenic (heterozygous for GJB2 combined with the GJB6 del( GJB6 -D13S11830) deletion) and autosomal dominant (n = 1) or heterozygous (n = 44/127, 34.6%) state. Of the 36 individuals with compound heterozygous variants, 3 had only one of the variants rated as pathogenic. Of the 44 individuals with heterozygous variants, 22 had variants that were pathogenic or likely pathogenic and 22 had variants that were of unknown significance, benign or likely benign. These 47 individuals were included in the demographic analysis but were treated separately in the genotype-phenotype analysis. In total, only 80 individuals were biallelic for pathogenic/likely pathogenic variants including one heterozygous with autosomal dominant inheritance. Three recurrent variants, c.109G > A p(Val37Ile), c.35delG p.(Gly12Valfs*2), and c.101T > C p.(Met34Thr) accounted for 48.4% (n = 77/159), 31.4% (n = 50/159) and 15.5% (n = 25/159) of all pathogenic or likely pathogenic variant alleles respectively. Furthermore, the c.109G > A variant accounted for the majority of homozygous cases (n = 32/45, 71.1%). (See Fig. 1 b). Table 1 demonstrates the distribution of the variants in the cohort for the 80 individuals with biallelic variants. Details of the remaining 47 individuals are presented in Supplementary Table 2. Table 1 Genotypes and phenotypes with age at genetic testing for individuals with biallelic or heterozygous (autosomal dominant) variants in GJB2 NM_004004.5 (NP_003995.2) n=80 Zygosity Age at genetic testing (years) Variant(s) Initial HL degree (better ear) Latest HL degree (better ear) ACMG ClinVar GnoMAD MAF Autosomal Dominant 0 years, 5 months c.551G > A p.(Arg184Gln) mod-severe severe P P not found Homozygous 0 years, 3 months c.35delG p.(Gly12Valfs*2) profound profound P P 0.005 0 years, 2 months profound profound 0 years, 3 months mod mod 0 years, 2 months severe missing 0 years, 2 months mild missing 0 years, 3 months mod-severe severe 0 years, 2 months severe severe 0 years, 6 months mod-severe mod-severe 0 years, 1 months mod-severe mod-severe 0 years, 2 months profound profound 0 years, 2 months mod-severe mod-severe 9 years, 4 months c.109G > A p.(Val37Ile) mild mild P P 0.007 3 years, 8 months mild mild 7 years, 3 months mild mild 7 years, 2 months mild mild 6 years, 6 months mild mild 2 years, 8 months normal normal 2 years, 1 months mild missing 3 years, 11 months mild mild 2 years, 4 months normal mild 13 years, 9 months mild mild 0 years, 8 months mod mod-severe 0 years, 3 months mild mild 0 years, 1 months mild mild 0 years, 6 months mild mild 0 years, 2 months mild mild 2 years, 11 months normal normal 2 years, 6 months missing mild 0 years, 1 months normal normal 1 years, 4 months normal missing 0 years, 2 months mod mod 0 years, 4 months mild mild 0 years, 8 months mild mild 0 years, 2 months mild mild 0 years, 4 months mild mild 0 years, 2 months mild mild 1 years, 3 months mild mild 0 years, 5 months mild mild 0 years, 4 months mild mild 0 years, 5 months mild mild 0 years, 3 months mod mod 0 years, 3 months normal normal 0 years, 2 months mild mild 0 years, 4 months c.101T > C p.(Met34Thr) mild missing P P 0.008 0 years, 3 months mild mild Compound heterozygous or Digenic (pathogenic variants) 0 years, 2 months c.71G > A p.(Trp24*) c.250G > C p.(Val84Leu) profound profound P P P P 0.00002 0.00004 0 years, 1 months c.71G > A p.(Trp24*) c.458_475dup p.(Val153_Tyr158dup) profound profound P P P P 0.00002 not reported 5 years, 8 months c.101T > C p.(Met34Thr) c.109G > A p.(Val37Ile) mild mild P P P P 0.008 0.007 0 years, 1 months c.101T > C p.(Met34Thr) c.298C > Tp.(His100Tyr) mod mod P P P P 0.008 0.00001 4 years, 1 months c.109G > A p.(Val37Ile) c.508_511dup p.(Ala171Glufs*40) normal mild P P P P 0.007 0.00001 0 years, 3 months c.235delC p.(Leu79Cysfs*3) c.299_300delAT p.(His100Argfs*14) mod mod P P P P 0.0005 0.00006 0 years, 4 months c.250G > C p.(Val84Leu) c.-23 + 1G > A mod mod P P P P 0.00004 0.0002 0 years, 2 months c.35delG p.(Gly12Valf*2) c.-23 + 1G > A mild missing P P P P 0.005 0.0002 0 years, 6 months c.35delG p.(Gly12Valf*2) c.101T > C p.(Met34Thr) normal mild P P P P 0.005 0.008 1 years, 4 months mild mild 0 years, 2 months mod mod 0 years, 2 months mild missing 6 years, 11 months mild mild 5 years, 6 months mild mild 1 years, 5 months normal mild 0 years, 2 months mod mod 0 years, 3 months mild missing 0 years, 2 months mild mild 3 years, 7 months mild missing 17 years, 8 months c.35delG p.(Gly12Valfs*2) c.139G > T p.(Glu47*) mod-severe missing P P P P 0.005 0.0001 0 years, 1 months mod severe 10 years, 10 months c.35delG p.(Gly12Valfs*2) c.109G > A p.(Val37Ile) mod mod P P P P 0.005 0.007 0 years, 6 months mild mild 0 years, 7 months c.35delG p.(Gly12Valfs*2) c.313_326del p.(Lys105Glyfs*5) profound missing P P P P 0.005 0.0001 0 years, 1 months c.35delG p.(Gly12Valfs*2) c.269T > C p.(Leu90Pro) mild missing P P P P 0.005 0.0006 4 years, 2 months normal mild 0 years, 1 months mild missing 0 years, 3 months mild mild 0 years, 3 months c.35delG p.(Gly12Valfs*2) c.169C > T p.(Gln57*) mild mild P P P P 0.005 0.00003 0 years, 3 months c.35delG p.(Gly12Valf*2) c.235delC p.(Leu79Cysfs*3) mod-severe mod-severe P P P P 0.005 0.0005 0 years, 2 months c.109G > A p.(Val37Ile) c.583A > G p.(Met195Val) mild normal P LP P 0.007 0.00003 0 years, 2 months c. 34G > T p.(Gly12Cys) c.109G > A p.(Val37Ile) mild normal LP P LP P 0.0005 0.007 1 years, 1 months c.101T > C p.(Met34Thr) c.194A > G p.(Tyr65Cys) mild normal P LP P LP 0.008 0.00001 0 years, 2 months c.101T > C p.(Met34Thr) del(GJB6-D13S11830) mild mild P P P P 0.008 not found A single patient carried del( GJB6 -D13S11830), in conjunction with a GJB2 c.101T > C variant. The autosomal dominant variant, c.551G > A, was identified in a case whose mother also had SNHL and had been previously reported in association with DFNA3.[ 23 ] Biallelic cases: Hearing profiles The specific genotype-phenotype analysis was performed on 80 individuals with biallelic or an autosomal dominant variant. The mean age at testing for this group was 1.8 years with a median age at testing of 4 months. The most frequent loss in the better ear was mild 43/80 (53.8%), with 10/80 initially coded as normal in the better hearing ear (12.5%), 11/80 moderate (13.8%), 7/80 moderately severe (8.8%), 2/80 severe (2.5%) and 6/80 profound (7.5%) (Fig. 1 a). For the initial hearing assessments, one patient had missing data, but was included because their subsequent audiogram was available. 60/80 patients had subsequent audiogram data available to evaluate change in hearing over time. Proportions of children in the severity categories was similar between initial and latest assessments. (Supplementary Fig. 1). Note that overall hearing was defined by the better hearing ear. 60 of the 80 patients in this group had information about stability and 49 of those had stable hearing profiles (49/60 = 81.6%) with most having mild hearing loss (n = 25/60, 41.6%). Two patients had fluctuating hearing profiles with mild hearing loss on their latest test (n = 2/60, 3.3%). Both individuals were homozygous for the c.109G > A variant. The other 9 individuals (n = 9/60, 15%) had progressive HL. Further information can be found in Table 2 a. Table 2a Genotype-phenotype correlations for progressive hearing loss n=15 (15/127 =11.8% of the cohort) Genotype Zygosity Number (%) of children Degree of HL initial Degree of HL latest Homozygous and compound heterozygous Pathogenic/Likely Pathogenic n = 9 c.551G > A p.(Arg184Gln) Autosomal dominant 1 moderately-severe severe c.109G > A p(Val37Ile) hmz 2 mild mild (deterioration in low frequencies) c.35delG p.(Gly12Valfs*2) hmz 1 moderately-severe severe c.35delG p.(Gly12Valfs*2) c.101T > C p.(Met34Thr) comp het 2 2 normal 2 mild (U-shaped) c.35delG p.(Gly12Valfs*2) c.139G > T p.(Glu47Ter) comp het 1 moderate severe (cochlear implants) c.35delG p.(Gly12Valfs*2) c.269T > C p.(Leu90Pro) comp het 1 normal mild c.109G > A p(Val37Ile) c.508_511dup p.(Ala171Glufs*40) comp het 1 normal mild (U-shaped) Heterozygous (pathogenic/likely pathogenic) n = 4 c.35delGp.(Gly12Valfs*2) het 1 mild moderate c.101T > C p.(Met34Thr) het 2 1 normal; 1 moderate 2 moderately-severe sloping c.313_326del p.(Lys105Glyfs*5) het 1 normal mild Heterozygous (likely benign/benign) n = 2 c.-216T > G p.(=) het 1 moderate Moderately -severe c.79G > A p.(Val27Ile) Het 1 normal severe Hmz = homozygous; comp het = compound heterozygous Table 2b Genotype Phenotype correlations with initial hearing loss coded as ‘normal’ (n = 25 25/127 = 19.6% of the cohort) Genotype Zygosity No of children Degree of HL initial ‘normal’ Degree of HL latest Homozygous and compound heterozygous (pathogenic/likely pathogenic) n = 10 c.109G > A p(Val37Ile) hmz 6 1 normal, 3 slight, 2 unilateral 1 unilateral, 3 slight 1 mild 1 missing c.109G > A p(Val37Ile) c.508_511dup p.(Ala171Glufs*40) comp het 1 unilateral bilat mild to mod 35delG p.(Gly12Valfs*2) c.101T > C p.(Met34Thr) comp het 2 unilateral Progressed to bilat U-shaped 35delG p.(Gly12Valfs*2) c.269T > C p.(Leu90Pro) comp het 1 normal bilat mild rising Compound heterozygous (one pathogenic variant) and heterozygous n = 7 c.109G > A p(Val37Ile) c.265C > Tp.(Leu89Phe) het 1 slight L normal c.109G > A p(Val37Ile) c.571T > C p.(Phe191Leu) het 1 Unilateral L high frequency L U-shaped, R rising 35delG p.(Gly12Valfs*2) het 2 1 unilateral, 1 slight 1 unilateral, 1 missing c.101T > C p.(Met34Thr) het 1 normal moderately-severe bilateral c.313_326del p.(Lys105Glyfs*5) het 1 unilateral high frequency bilateral mild c.514T > A p.(Trp172Arg) het 1 unilateral unilateral Heterozygous (VUS/LB/B) n = 8 c.79G > A p.(Val27Ile) het 5 1 normal, 2 unilateral, 1 slight, 1 temporary conductive 1 unilateral, 1 temporary conductive 1 bilateral profound 2 missing c.341A > G p.(Glu114Gly) c.79G > A p.(Val27Ile) het 1 unilateral missing c.-45C > A het 1 unilateral unilateral c.-130C > G het 1 temporary conductive temporary conductive Comp het = compound heterozygous; VUS = variant of uncertain significance; LB = likely benign; B = benign Ten of 80 (12.5%) patients demonstrated hearing that was coded as ‘normal’ in the better hearing ear at their initial hearing test. The genotype and further information about HL in these individuals is presented in Table 2 b. The majority of these individuals had progression of their HL. Heterozygous cases: Hearing profiles The hearing profiles in heterozygous cases can be seen in Supplementary Table 2, Fig. 1 a and Supplementary Fig. 1b. Of the 47 individuals with heterozygous variants and those with variants of uncertain significance or likely benign, the hearing profiles were similar between the initial and latest assessment with nine not having follow up audiogram data. The proportions of HL severity at the initial time point were 15/47 (31.9%) normal in the better ear (more detail in Table 2 ) mild 21/47 (44.7%), moderate 8/47 (17%) and one each of moderately-severe (2.1%), severe (2.1%) and profound (2.1%) (Supplementary Fig. 1b). HL progression was assessable in 97 individuals (from both biallelic and heterozygous groups) who had audiograms at multiple time points and sufficient information to code HL stability. Progressive HL was seen in 15 total; 9/60 (15%) in the homozygous/compound heterozygous/AD group and 6/37 (16.2%) in the heterozygous/VUS/likely benign group. Genotypes of those individuals are presented in Table 2 a and include the autosomal dominant variant, homozygous and compound heterozygous c.35delG and c.109G > A as well as several other genotypes. Biallelic Cases: Genotype-Phenotype Associations The three most common variants had sufficient sample size for Pearson’s chi-squared or Fisher’s exact statistical test analysis for association between genotype and phenotypic characteristics and were all present in homozygous, compound heterozygous and heterozygous states (More detail in Table 1). Figure 1 a demonstrates the degree of initial HL by zygosity and 1b demonstrates the degree of initial HL for the three most frequent variants in homozygous state. The most frequent variant, c.109G > A, had sufficient numbers for analysis for phenotypic associations with both homozygous state and combination of homozygous/compound heterozygous, and c.35delG and c.101T > C had sufficient numbers for this analysis of homozygous/compound heterozygous state. Fisher exact statistical test analysis found that patients who were homozygous for c.109G > A were much more likely to have mild hearing loss and less moderately severe/severe/profound for both their initial and latest hearing tests (p = 0.0004 and 0.006 respectively) than the rest of the cohort. Individuals who were homozygous/compound heterozygous for the c.109G > A variant were also significantly more likely to have mild hearing loss (versus moderately-severe/severe/profound hearing loss) as compared to those not carrying the c.109G > A variant for both the initial (p = 0.00004) and most recent audiogram data (p = 0.0004) (Table 3 ). Table 3 Degree of HL initial and latest for patients (i) homozygous for GJB2 c.109G > A p.(Val37Ile), (ii) homozygous or compound heterozygous c.109G > A p.(Val37Ile) and (iii) homozygous or compound heterozygous c.35delG p(Gly12Valfs*2) variant present (Fisher’s exact statistical test) c. 109G > A hmz/comp het versus heterozygous or negative c.35delG hmz/comp het versus heterozygous/negative cases Characteristic Homozygous c.109G > A variant ( N = 32 † ) negative, comp het or het for c.109G > A (N = 48 † ) p-value* All Hmz and comp het c.109G > A (N = 38 † ) Negative or het for c.109G > A N = 42 † p-value* Hmz or comp het c.35delG (N = 34 † ) negative or het for c.35delG (N = 46 † ) p-value* Degree of Hearing Loss- Initial 0.0004 0.00004 0.007 Normal 6 (19%) 4 (8.3%) 7 (18.9%) 3 (7.1%) 3 (9.1%) 7 (15.2%) Mild 22 (71%) 21 (43.8%) 26 (70.2%) 17 (40.5%) 13 (39.4%) 30 (65.2%) Moderate 3 (9.7%) 8 (16.7%) 4 (10.8%) 7 (16.7%) 5 (15.2%) 6 (13%) Mod- Severe/Severe/Profound 0 (0%) 15 (31.3%) 0 (0%) 15 (35.7%) 12 (36.4%) 3 (6.5%) Unknown 1 0 1 0 1 0 Degree of Hearing Loss- Latest 0.006 0.0004 0.007 Normal 4 (13.3%) 3 (8.6%) 6 (16.7%) 1 (3.4%) 0 (%) 7 (16.7%) Mild 23 (76.7%) 15 (%) 26 (72.2%) 12 (41.4%) 11 (47.8%) 27 (64.3%) Moderate 2 (6.7%) 7 (20%) 3 (8.3%) 6 (20.7%) 4 (17.4%) 5 (11.9%) Moderately- Severe/Severe/Profound 1 (3.3%) 10 (28.6%) 1 (2.8%) 10 (34.5%) 8 (34.8%) 3 (7.1%) Unknown 2 13 2 13 11 4 * Fisher’s exact probability test Individuals who were homozygous/compound heterozygous for the c.35delG variant had significantly more moderately-severe/severe/profound hearing loss than those with other genotypes at both time points (p = 0.007 and 0.007 respectively) (Table 3 ). Individuals who were homozygous/compound heterozygous for the c.101T > C variant had significantly more U-shaped and sloping audiograms than other audiogram configurations at the most recent time point (p = 0.02) (Table 4 ). There were no other significant associations between genotype and any of the other audiology descriptors (audiogram shape, symmetry or stability). Table 4 Audiogram shape initial and latest for patients: c.101T > C p(Met34Thr) homozygous/compound heterozygous variant present (Fisher’s exact statistical test) Characteristic Hmz/comp het c.101T > C Present: N = 17 negative or het for c.101T > C N = 63 p-value* Audiogram shape- initial 0.14 Flat 7 (43.8%) 39 (61.9%) Rising 0 (0%) 5 (7.9%) Sloping 7 (43.8%) 17 (27%) U-shaped 2 (12.5%) 2 (3.2%) Unknown 1 0 Audiogram shape- Latest 0.02 Flat 3 (21.4%) 26 (53.1%) Rising 0 (0%) 4 (8.2%) Sloping 6 (42.9%) 15 (30.6%) U-shaped 5 (35.7%) 4 (8.2%) Unknown 3 14 * Fisher exact probability test Genotype-Phenotype association: progressive HL and ‘normal’ hearing Of the 10 individuals who were homozygous/compound heterozygous who had normal hearing in the better ear on the initial audiogram (Table 2 b), 6 were homozygous for c.109G > A. There were 2 individuals who were compound heterozygous for c.35delG/c.101T > C who had unilateral HL at the initial time point and bilateral U-shaped HL at the most recent time point. Six of the 15 individuals with progressive HL (Table 2 a) had at least one variant that was c.35delG. DISCUSSION This study reports variant data from a geographical region which has been understudied to date. State-wide newborn screening (99% coverage), and follow-up GJB2/6 testing in screen positive individuals revealed biallelic and heterozygous carriage in association with predominantly mild hearing loss. The most frequent variant, c.109G > A, has been described with mild phenotypes, and may partially explain the increase in mild hearing loss detected on newborn screening. Consistent with the literature, the c.35delG variant was associated with more severe HL, while the c.101T > C variant was associated with milder HL and U-shaped audiograms. This information provides a more complete picture of the phenotypic spectrum of GJB2/6 associated HL which provides short-term prognostic data and can inform pre- and post-natal counselling for individuals and families found to carry these variants. Ascertainment in this study differs from most previously reported literature which genetically evaluated individuals being considered for cochlear implants i.e., typically severe levels of hearing loss [ 24 , 25 ]. In those studies, the most common variants were c.35delG and c.235delC which were identified in populations from European and Asian backgrounds, respectively. The c.109G > A variant has been reported previously, especially from Asian ancestry cohorts [ 26 ], where the minor allele frequency is 0.08 [ 27 ]. Thus, it is unsurprising that it is prevalent in our agnostically ascertained cohort where the sensitive equipment used for universal newborn hearing screening and aABR (automated auditory evoked brainstem response) as a screening method can lead to capturing patients that may have mild, transient and/or fluctuating hearing profiles. An artefact of newborn screening is the detection of mild hearing loss. As mild hearing-loss is being increasingly diagnosed at an earlier age [ 28 ], this presents prognostic and management uncertainty for both families [ 29 ] and clinicians [ 30 ]. This study provides evidence for a genetic basis for many mild hearing loss cases adding to the emerging body of literature describing genotypes in mild and moderate hearing loss cohorts [ 31 , 32 ]. Prior publications have noted milder hearing loss in association with either c.101T > C or c.109G > A alleles [ 33 ]. The pathogenic classifications of both variants were initially controversial, but an international consensus paper classified both as pathogenic with variable expressivity and incomplete penetrance [ 34 ]. Consistently, in this Australian cohort this variant is associated with a milder phenotype. This phenotypic information is valuable for clinicians and families presented with these results in infancy, prenatally or as part of reproductive carrier screening [ 35 ]. Previous research has shown that a heterozygous GJB2 variant is detected in 10–50% of individuals with hearing loss [ 36 ], which can complicate and limit clinical interpretation and management. Additionally, some studies have indicated that carriers of certain variants have been reported to be more likely than ‘non-carriers’ to develop hearing impairment when exposed to other environmental factors or genetic defects [ 37 ]. In the current study, heterozygosity was identified in 37% of the cohort and the associated hearing loss phenotype was highly variable ranging from normal (in the better ear) to profound. These findings align with previous publications [ 33 ] and may be due to (i) the GJB2 variant being coincidental, with hearing loss secondary to variants in another NSHL gene, (ii) failure to detect a second, possibly intronic functionally significant variant in GJB2 , (iii) the GJB2 variant modifies the expression of other variants in related hearing loss genes or (iv) the GJB2 variant being coincidental and the hearing loss stemming from a non-genetic aetiology. Comprehensive panel testing and/or whole genome sequencing may help identify the first two possibilities [ 38 ], and further research could possibly elucidate the third. It is important to appreciate that classification of hearing loss in this study is relative to the better hearing ear. Thus, our study detected individuals with normal hearing and asymmetric hearing loss where the hearing of the contralateral ear could range from mild to profound. The fact that genetic testing was offered in these cases implies that the hearing loss was, at the time of testing, considered to be clinically indicated and/or socially significant to the individual or their families. While hearing loss in some cases may have been complicated by transient, conductive overlay, the findings from the present study support that GJB 2 variants can be associated with asymmetric hearing loss [ 8 ]. The identification of these asymmetric cases (where one ear is classified as ‘normal’ hearing) may be reduced from this point forward given recommendations to only offer genetic testing in cases of bilateral hearing loss [ 39 ]. However, a uniform and consistent approach to genetic testing for patients with NSHL is important to mitigate the risk of uncertain findings. Furthermore, this could potentially reduce the financial and psychological costs associated with inappropriate genetic testing. The natural history in this cohort was predominantly stable but shows both improvements and progression over time. These findings are consistent with those previously reported in the literature [ 8 , 40 ]. However, it should be noted that audiogram results become more accurate with increasing age in children, thus fluctuation/progression may reflect the young age of this cohort. Importantly, U-shaped hearing loss was identified more frequently at subsequent time points than initial assessments and was associated with c.101T > C. There is a paucity of literature on U-shaped (mid-frequency) hearing loss, an uncommon audiometric finding, more commonly diagnosed in older individuals [ 41 ]. Although U-Shaped hearing loss has not been formally associated with GJB2 generally and the c.101T > C variant specifically, in reviewing previously published audiograms in c.101T > C positive individuals [ 42 ], we identified cases of U-Shaped hearing loss. This is clinically significant because this mid-frequency loss is associated with greater difficulty understanding speech in a noisy environment such as a classroom setting. Thus, children may function differentially in quiet and noisy environments, which could mask detection, thus increasing the risk of social problems and fatigue, especially if it is a deterioration [ 43 ]. Cumulatively, these results demonstrate a broad phenotypic association with GJB2 variants and some genotype-phenotype associations which can provide prognostic value. This data from a population wide cohort, provides prognostic information for preconception, prenatal and paediatric counselling of couples and families carrying these variants. For example, Freeman et al.’s [ 44 ] discussion of views regarding genetic testing for deafness in reproductive settings, highlighted that the recent American College of Medical Genetics and Genomics practice guidelines [ 35 ] recommended the inclusion of GJB2 variants in prenatal genetic screening on the basis of prevalence and NSHL being categorised as ‘moderately severe’ [ 45 ]. If such guidelines were adopted in Australia, the information in studies like this would be invaluable in counselling. Strengths of this study include the agnostic mode of ascertainment which allowed for identification of a broad phenotypic spectrum. The centralisation of newborn screening, pathology and clinical data allowed for comprehensive phenotypic characterisation. Limitations include a finite sample size and follow up period, lack of detailed data about other potentially contributing factors for HL and the fact that testing was limited to GJB2 coding variants and a single GJB6 deletion. Future directions to further assist clinicians in providing genetic counselling in this area could include longer follow-up to clarify stability over time, broadening the phenotype to include developmental outcomes including speech and language development and response to intervention e.g., documenting outcomes of children who have required cochlear implants, and comprehensive panel testing for hearing loss. Cumulatively, this information would provide clinicians and families with greater prognostic and management certainty at the time of diagnosis. Conclusion This study provides valuable insights for managing and counselling individuals with GJB2/GJB6 variants. The phenotypic spectrum in biallelic individuals in this cohort is milder than has been previously reported, likely due to the agnostic ascertainment. Conversely, our study identified a portion of heterozygous carriers experienced hearing loss, which ranged from mild to moderate. The publication of the full spectrum of presentations offsets the prior publication of more severe presentations, which has potentially skewed the overall perception of the severity of the condition. Given the increasing interest in pre-conception carrier testing for deafness, larger cohort data is crucial to provide personalised, accurate genetic counselling. Declarations Conflict of Interest None Funding This research did not receive any specific grants from funding agencies in the public, commercial or not-for profit sectors. Data Availability Statement The data are available in Table 1 and Supplementary Table 2 and the variants have been submitted to ClinVar SUB13514054. Author contributions RK: literature review, extracted, collated and cleaned data, performed descriptive statistics, drafted initial manuscript and edited revisions RB: provided advice on design and development of study, reviewed and revised manuscript MTG: curated variant impact, reviewed and revised manuscript AML: supervised variant analysis, revised and edited drafts CD: edited the draft KL: conceptualised and designed the study, extracted clinical data, performed descriptive statistics, reviewed and revised manuscript Acknowledgements The authors would like to acknowledge Ben Lundie, Chiyan Lau for help extracting genetic data, Megan Moore and Jane Fitzgibbons for help extracting audiological data and Ella McGahan for help with formatting and proof reading References Rouse, S.L., et al., Racial and ethnic disparities in genetic testing for hearing loss: a systematic review and synthesis. Hum Genet, 2022. 141 (3-4): p. 485-494. World Health Organisation., World report on hearing . 2021: Geneva. Brewer, C.C. and K.A. King, Genetic hearing loss: the audiologist's perspective. Hum Genet, 2022. 141 (3-4): p. 311-314. Van Camp, G., P.J. Willems, and R.J. Smith, Nonsyndromic hearing impairment: unparalleled heterogeneity. Am J Hum Genet, 1997. 60 (4): p. 758-64. Van Camp, G. and R.J. Smith. Hereditary Hearing Loss Homepage . Deafness, Autosomal Recessive 1A DFNB1A 30 August 2021 [cited 2022 March 19]; Available from: https://omim.org/entry/220290. Putcha, G.V., et al., A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genetics in Medicine, 2007. 9 (7): p. 413-426. DeMille, D., et al., Three novel GJB2 (connexin 26) variants associated with autosomal dominant syndromic and nonsyndromic hearing loss. Am J Med Genet A, 2018. 176 (4): p. 945-950. Chan, D.K. and K.W. Chang, GJB2-associated hearing loss: systematic review of worldwide prevalence, genotype, and auditory phenotype. Laryngoscope, 2014. 124 (2): p. E34-53. Michalski, N. and C. Petit, Central auditory deficits associated with genetic forms of peripheral deafness. Human Genetics, 2022. 141 (3): p. 335-345. Tsukada, K., et al., Ethnic-specific spectrum of GJB2 and SLC26A4 mutations: their origin and a literature review. Ann Otol Rhinol Laryngol, 2015. 124 Suppl 1 : p. 61S-76S. Adadey, S.M., et al., Connexin Genes Variants Associated with Non-Syndromic Hearing Impairment: A Systematic Review of the Global Burden. Life (Basel), 2020. 10 (11). Dahl, H.-H.M., et al., Etiology and audiological outcomes at 3 years for 364 children in Australia. PloS one, 2013. 8 (3): p. e59624-e59624. Fitzgibbons, E.J., et al., Childhood hearing loss detected beyond the newborn screen. Int J Audiol, 2023. 62 (3): p. 278-285. Australian Bureau of Statistics. Cultural diversity: Census 2021; Available from: https://www.abs.gov.au/statistics/people/people-and-communities/cultural-diversity-census/2021. Landrum, M.J., et al., ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res, 2018. 46 (D1): p. D1062-d1067. Azaiez, H., et al., Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. Am J Hum Genet, 2018. 103 (4): p. 484-497. Kopanos, C., et al., VarSome: the human genomic variant search engine. Bioinformatics, 2018. 35 (11): p. 1978-1980. Li, M.M., et al., Clinical evaluation and etiologic diagnosis of hearing loss: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med, 2022. 24 (7): p. 1392-1406. Goodman, A., Reference zero levels for pure tone audiometers. ASHA, 1965. 7 : p. 262-263. Clark, J.G., Uses and abuses of hearing loss classification. ASHA, 1981. 23 (7): p. 493-500. Guo, C., et al., Hearing Phenotypes of Patients with Hearing Loss Homozygous for the GJB2 c.235delc Mutation. Neural Plast, 2020. 2020 : p. 8841522. Pittman, A.L. and P.G. Stelmachowicz, Hearing loss in children and adults: audiometric configuration, asymmetry, and progression. Ear Hear, 2003. 24 (3): p. 198-205. Weegerink, N.J., et al., Phenotypes of two Dutch DFNA3 families with mutations in GJB2. Ann Otol Rhinol Laryngol, 2011. 120 (3): p. 191-7. Popov, T.M., et al., Auditory outcome after cochlear implantation in patients with congenital nonsyndromic hearing loss: influence of the GJB2 status. Otol Neurotol, 2014. 35 (8): p. 1361-5. Sinnathuray, A.R., et al., Connexin 26 (GJB2) gene-related deafness and speech intelligibility after cochlear implantation. Otol Neurotol, 2004. 25 (6): p. 935-42. Dahl, H.H., et al., The contribution of GJB2 mutations to slight or mild hearing loss in Australian elementary school children. J Med Genet, 2006. 43 (11): p. 850-5. Chen, S., et al., A genome-wide mutational constraint map quantified from variation in 76,156 human genomes. bioRxiv, 2022: p. 2022.03.20.485034. McKay, S., J.S. Gravel, and A.M. Tharpe, Amplification Considerations for Children With Minimal or Mild Bilateral Hearing Loss and Unilateral Hearing Loss. Trends in Amplification, 2008. 12 (1): p. 43-54. Lin, J.J., et al., Mild matters: parental insights into the conundrums of managing mild congenital hearing loss. Int J Audiol, 2022. 61 (6): p. 500-506. Ching, T.Y.C., et al., Audiologists' perspectives on management of mild bilateral hearing loss in infants and young children. Int J Audiol, 2022. 61 (9): p. 752-760. Kim, B.J., et al., Significant Mendelian genetic contribution to pediatric mild-to-moderate hearing loss and its comprehensive diagnostic approach. Genet Med, 2020. 22 (6): p. 1119-1128. Markova, T., et al., Audiological Evidence of Frequent Hereditary Mild, Moderate and Moderate-to-Severe Hearing Loss. J Pers Med, 2022. 12 (11). Kenna, M.A., et al., Audiologic phenotype and progression in GJB2 (Connexin 26) hearing loss. Arch Otolaryngol Head Neck Surg, 2010. 136 (1): p. 81-7. Shen, J., et al., Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel. Genet Med, 2019. 21 (11): p. 2442-2452. Gregg, A.R., et al., Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med, 2021. 23 (10): p. 1793-1806. Del Castillo, I., et al., Prevalence and evolutionary origins of the del(GJB6-D13S1830) mutation in the DFNB1 locus in hearing-impaired subjects: a multicenter study. Am J Hum Genet, 2003. 73 (6): p. 1452-8. Abdurehim, Y., A. Lehmann, and A.G. Zeitouni, Predictive Value of GJB2 Mutation Status for Hearing Outcomes of Pediatric Cochlear Implantation. Otolaryngol Head Neck Surg, 2017. 157 (1): p. 16-24. Lin, Y.H., et al., Hearing Impairment with Monoallelic GJB2 Variants: A GJB2 Cause or Non-GJB2 Cause? J Mol Diagn, 2021. 23 (10): p. 1279-1291. Sung, V., et al., Childhood Hearing Australasian Medical Professionals network: Consensus guidelines on investigation and clinical management of childhood hearing loss. J Paediatr Child Health, 2019. 55 (9): p. 1013-1022. Del Castillo, F.J. and I. Del Castillo, DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes. Front Mol Neurosci, 2017. 10 : p. 428. Birkenbeuel, J., et al., Characteristics of Mid-Frequency Sensorineural Hearing Loss Progression. Otol Neurotol, 2019. 40 (5): p. e497-e502. Snoeckx, R.L., et al., GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet, 2005. 77 (6): p. 945-57. Tharpe, A.M. and R. Seewald, Comprehensive Handbook of Pediatric Audiology . 2016, San Diego, UNITED STATES: Plural Publishing, Inc. Freeman, L., et al., The views of people with a lived experience of deafness and the general public regarding genetic testing for deafness in the reproductive setting: A systematic review. Genet Med, 2022. 24 (9): p. 1803-1813. Lazarin, G.A., et al., Systematic Classification of Disease Severity for Evaluation of Expanded Carrier Screening Panels. PLoS One, 2014. 9 (12): p. e114391. Additional Declarations There is no duality of interest Supplementary Files SupplementarymaterialJan12.docx Supplementary material Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: revise 30 Jan, 2024 Review # 2 received at journal 25 Jan, 2024 Review # 1 received at journal 23 Jan, 2024 Reviewer # 2 agreed at journal 18 Jan, 2024 Reviewer # 1 agreed at journal 17 Jan, 2024 Reviewers invited by journal 15 Jan, 2024 Submission checks completed at journal 15 Jan, 2024 First submitted to journal 12 Jan, 2024 Unknown event 11 Jan, 2024 Editor assigned by journal 02 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3829481","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":267241401,"identity":"d78a6d1c-089b-4f99-958e-a730699645e0","order_by":0,"name":"Karen Liddle","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAz0lEQVRIiWNgGAWjYBACCQbmhgM8bBYM/GAuG1FaGEFaJBgkG0jRwgDSYnCAWC2SDYyNB96UScgZ30jewPCh7DAD/4wE/FqkgbYcnHNOwtjsRloB44xzhxkkbhDQIgfUcpi3TSJx240cA2betsMMDMRqqd88A6jlL1CLPCEt0lAtCQYSQC2MQC0GhLRINkP8YjjjzLOCgz3n0nkMzzzAr0XiePPhD2/KbOT525M3PvhRZi0nd5yALQzMCCY4angIqEcFBiSpHgWjYBSMgpEDAHS9QlNYNxmzAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-1948-5872","institution":"Queensland Children's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Karen","middleName":"","lastName":"Liddle","suffix":""},{"id":267241402,"identity":"aff5d5da-1c14-4e5c-a249-a18949a15c1d","order_by":1,"name":"Rebecca Kriukelis","email":"","orcid":"","institution":"Queensland Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Rebecca","middleName":"","lastName":"Kriukelis","suffix":""},{"id":267241403,"identity":"909732ae-a1a5-4295-9881-0f82db6d1185","order_by":2,"name":"Michael Gabbett","email":"","orcid":"","institution":"Queensland University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Gabbett","suffix":""},{"id":267241404,"identity":"3e96f3ce-6fbd-47dc-ba67-26a98439d823","order_by":3,"name":"Rachael Beswick","email":"","orcid":"","institution":"Children's Health Queensland","correspondingAuthor":false,"prefix":"","firstName":"Rachael","middleName":"","lastName":"Beswick","suffix":""},{"id":267241405,"identity":"6c439db2-4d3d-4b3a-8acc-84ea203944d7","order_by":4,"name":"Aideen McInerney-Leo","email":"","orcid":"https://orcid.org/0000-0002-0059-5732","institution":"The University of Queensland","correspondingAuthor":false,"prefix":"","firstName":"Aideen","middleName":"","lastName":"McInerney-Leo","suffix":""},{"id":267241406,"identity":"8aa2c164-e885-4558-b2d7-ebdc5c3d4ab9","order_by":5,"name":"Carlie Driscoll","email":"","orcid":"","institution":"University of Queensland","correspondingAuthor":false,"prefix":"","firstName":"Carlie","middleName":"","lastName":"Driscoll","suffix":""}],"badges":[],"createdAt":"2024-01-02 12:22:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3829481/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3829481/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49762822,"identity":"907cc419-954e-4ff4-8099-6d751e2d47e9","added_by":"auto","created_at":"2024-01-17 16:14:32","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":699176,"visible":true,"origin":"","legend":"\u003cp\u003eGenotype Phenotype: Initial HL by zygosity\u003c/p\u003e\n\u003cp\u003e(a) Whole cohort\u003c/p\u003e\n\u003cp\u003e(b) Homozygous group\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3829481/v1/893958231eb67d6c04146fd0.jpg"},{"id":49763755,"identity":"aab9346c-281d-468d-9759-f98ccbbe5091","added_by":"auto","created_at":"2024-01-17 16:22:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":519919,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3829481/v1/91f39008-e294-4554-b0a9-59a9a7149b9c.pdf"},{"id":49762152,"identity":"9cf659e5-9317-42c5-99cf-0f7c6ba0ee96","added_by":"auto","created_at":"2024-01-17 16:06:32","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":49203,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary material\u003c/p\u003e","description":"","filename":"SupplementarymaterialJan12.docx","url":"https://assets-eu.researchsquare.com/files/rs-3829481/v1/a2d03d10b042848116b02d48.docx"}],"financialInterests":"There is no duality of interest","formattedTitle":"The congenital hearing phenotype in GJB2 in Queensland, Australia: V37I and mild hearing loss predominates","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eSensorineural hearing loss is the most common congenital sensory disorder, affecting 1 in 500 newborns [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. It can adversely affect language development, cognition, psychosocial wellbeing and quality of life, educational attainment, and economic independence at various stages of life[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Approximately 50% of congenital hearing loss is Mendelian, with 30% of individuals having a recognised syndrome and 70% regarded as non-syndromic [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNon-syndromic hearing loss (NSHL) is heterogeneous with approximately 75% of early onset cases being inherited in an autosomal recessive manner [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Seventy-eight of the 124 NSHL genes are autosomal recessive [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], and the most frequently implicated gene is \u003cem\u003eGJB2\u003c/em\u003e (OMIM 121011), which is responsible for the protein gap junction protein beta-2 (connexin 26). However, a single \u003cem\u003eGJB2\u003c/em\u003e variant can lead to disease if coinherited with a variant in the contiguous gene \u003cem\u003eGJB6\u003c/em\u003e, (OMIM 604418) gap junction protein beta-6 (connexin 30) in approximately 2% of cases [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In addition, pathogenic variants in GJB2 can be associated with autosomal dominant inheritance in approximately 2% of cases [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWorldwide, \u003cem\u003eGJB2\u003c/em\u003e pathogenic variants account for 18%-50% of prelingual NSHL. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] In addition, \u003cem\u003eGJB2\u003c/em\u003e variants account for 30\u0026ndash;50% of all cases of profound NSHL [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Widespread testing of \u003cem\u003eGJB2\u003c/em\u003e (and \u003cem\u003eGJB6\u003c/em\u003e), reveals variable degrees of hearing loss (mild to profound), not always detectable at birth, which is usually bilateral, but occasionally unilateral, and can be progressive [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevious cohort studies identified a recurrent variant in \u003cem\u003eGJB2\u003c/em\u003e (c.35delG) estimated to account for approximately 60\u0026ndash;70% of deafness in European, North African, Middle Eastern, Asian, North and South American populations [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. A single study in an Australian paediatric population identified the c.35delG variant to be the most frequently implicated (38.03%) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Other \u003cem\u003eGJB2\u003c/em\u003e variants have been implicated in other populations. Specifically, the c.235delC and c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A \u003cem\u003eGJB2\u003c/em\u003e variants are more frequently implicated in hearing loss in East Asian countries including Japan, Korea and China [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere is significant genotypic and phenotypic variability in international studies, but limited data from Oceania. Of note, a recent systematic review identified that only 0.7% of publications about connexin gene variants were from Australia [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Thus, this study reviewed all \u003cem\u003eGJB2\u003c/em\u003e positive cases from the Queensland state laboratory, documented all \u003cem\u003eGJB2\u003c/em\u003e and \u003cem\u003eGJB6\u003c/em\u003e genotypes, and reviewed audiological and clinical data to identify possible genotype-phenotype correlations for a Queensland paediatric population with NSHL.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthical Considerations\u003c/h2\u003e \u003cp\u003e This study was conducted in full conformance with principles of the \u0026lsquo;Declaration of Helsinki\u0026rsquo; Good Clinical Practice and was approved by the Children\u0026rsquo;s Health Queensland Hospital and Health Service Human Research Ethics Committee (Protocol Number HREC/20/QCHQ/65404).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy population and context\u003c/h2\u003e \u003cp\u003eQueensland is an Australian state, where 99% of the 60 000 babies born each year, have newborn hearing screening as part of a state-government funded program (\u0026lsquo;Healthy Hearing Program\u0026rsquo;). Screen positive individuals are referred for follow up diagnostic assessment in accordance with a state-wide protocol \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.childrens.health.qld.gov.au/resources/our-work/healthy-hearing/queensland-health-screening-protocols-and-guidelines\u003c/span\u003e\u003cspan address=\"https://www.childrens.health.qld.gov.au/resources/our-work/healthy-hearing/queensland-health-screening-protocols-and-guidelines\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. This study includes children diagnosed with a hearing impairment through this pathway or those diagnosed with hearing loss in later childhood (either through the targeted surveillance program or external referral). Included individuals were seen in specialised paediatric ENT and/or medical hearing loss clinics at Queensland Children\u0026rsquo;s Hospital and other public hospitals statewide who had subsequent genetic testing with Pathology Queensland. All individuals had undergone genetic testing between November 2014 and December 2019. Medical and audiological records of this paediatric population were retrospectively reviewed. Ancestral background information was not routinely available; however, recent census data shows that whilst English and Australian ancestry is more common (33.6% and 31.2% respectively), Chinese ancestry is the 5th most common in Australia (5.5% in the 2021 census), with a recent increase in the proportion of first-generation Chinese born people residing in Australia. Of note, First Nations peoples (Aboriginal and Torres Strait Islander peoples) were recorded at 3.2% of 2021 census [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eGenetic Testing\u003c/h2\u003e \u003cp\u003ePathology Queensland is a state-wide service offering genetic testing for individuals diagnosed with hearing loss. Specifically, the entire coding region of \u003cem\u003eGJB2\u003c/em\u003e is sequenced (Sanger sequencing) for all patients and no further testing is conducted on individuals found to carry biallelic variants. When \u003cem\u003eGJB2\u003c/em\u003e heterozygosity is identified, there is subsequent screening for a single \u003cem\u003eGJB6\u003c/em\u003e deletion (del(\u003cem\u003eGJB6\u003c/em\u003e-D13S11830) due to the interactive association. The study was confined to all patients that undertook \u003cem\u003eGJB2\u003c/em\u003e and \u003cem\u003eGJB6\u003c/em\u003e testing during the study period. Patients with no detected variants were excluded from the study.\u003c/p\u003e \u003cp\u003eMedical records were reviewed for all cases including homozygous/compound heterozygous and heterozygous cases or a single \u003cem\u003eGJB2\u003c/em\u003e variant in the presence of a \u003cem\u003eGJB6\u003c/em\u003e deletion. Variant pathogenicity was initially evaluated by reviewing ClinVar [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and the Deafness Variation Database [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] to determine prior association with disease. For all variants not reported in ClinVar, a Varsome assessment [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] rated their likely pathogenicity using the American College of Medical Genetics and Genomics guidelines and best practices for expert interpretation of genomic data [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Based on these categories individuals were classified as autosomal dominant pathogenic variant, homozygous for pathogenic variants, compound heterozygous for two pathogenic variants, compound heterozygous for two variants (at least one pathogenic), digenic (one \u003cem\u003eGJB2\u003c/em\u003e, one \u003cem\u003eGJB6\u003c/em\u003e), heterozygous for pathogenic/likely pathogenic variants or heterozygous for VUS/likely benign/benign variant. The hearing profiles were included for all variant carriers, but statistical analyses (see below) were limited to individuals with biallelic pathogenic/likely pathogenic variants.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eHearing assessment\u003c/h2\u003e \u003cp\u003eInformation relating to the severity of hearing impairment and a description of the audiogram was collated. The sensorineural (permanent) component of the HL was used in the cases with mixed (both sensorineural and conductive) HL, and we aimed to exclude temporary conductive HL, but the distinction was not always apparent during early testing. Degrees of hearing loss were based on the classification system outlined by Goodman and Clark and include normal (\u0026le;\u0026thinsp;20 dB HL), mild (21\u0026ndash;40 dB HL), moderate (41\u0026ndash;55 dB HL), moderately severe (56\u0026ndash;70 dB HL), severe (71\u0026ndash;90 dB HL), and profound (\u0026gt;\u0026thinsp;90 dB HL). A four-frequency average was used to determine the degree of hearing loss. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] The audiograms were also assessed for shape (rising, sloping/descending, flat, U-shaped), symmetry (symmetrical, asymmetrical) and stability (fluctuating, progressive, stable). [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] (See Supplementary Table\u0026nbsp;1 for definitions of descriptors). If the hearing loss was asymmetrical, it was graded according to the better hearing side. Audiometric testing was performed using a variety of age-appropriate standardised techniques for paediatric populations \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.childrens.health.qld.gov.au/resources/our-work/healthy-hearing/audiology-diagnostic-assessment-protocol\u003c/span\u003e\u003cspan address=\"https://www.childrens.health.qld.gov.au/resources/our-work/healthy-hearing/audiology-diagnostic-assessment-protocol\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In cases where consecutive reports were available, the stability of the hearing loss was also documented, by comparing audiogram results from the initial and most recent hearing assessment. Only patients with copies of audiograms in their medical record were included in the study. Audiology data was confirmed and supplemented through review of the QChild database, Queensland\u0026rsquo;s newborn hearing screening data management system which contains demographic and clinical information from screening.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eAll genetic and phenotypic data (extracted from patient medical records and QChild) were exported into Microsoft Excel. A descriptive statistical analysis was performed. Fisher exact statistical tests were used to determine whether specific genotypes were more frequently associated with milder or more severe audiological phenotypes as well as other audiological descriptors. Specific genotype-phenotype analysis was performed for individuals who had pathogenic or likely pathogenic variants that were inherited in a homozygous, compound heterozygous or autosomal dominant manner. Moderately-severe, severe and profound HL were grouped together due to sample size limitations. A p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy Population\u003c/h2\u003e\n\u003cp\u003eOf the 625 individuals with \u003cem\u003eGJB2\u003c/em\u003e +/- \u003cem\u003eGJB6\u003c/em\u003e sequencing through Pathology Queensland during the study period (2014 to 2019), 134 had variants detected and sufficient audiological information. After review of patient medical records and QChild, seven patients had other known identifiable causes for their hearing impairment (three with absent cochlear nerves, two with enlarged vestibular aqueducts, one with Waardenburg syndrome and another with a chromosome 15q11.1 deletion) and were excluded. This left a total of 127 patients for analysis.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003eDemographics\u003c/h2\u003e\n\u003cp\u003eThe final 127 cohort consisted of 72 males and 55 females. The mean age at genetic testing was 1.8 years with the range between 2 months and 17 years. The median age of genetic testing was 4 months with 68% of the cohort having the testing under 12 months of age. Specific information about ancestral background was not consistently available.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003eGenetic Findings:\u003c/h2\u003e\n\u003cp\u003eIn the cohort of 127 patients, 36 different \u003cem\u003eGJB2\u003c/em\u003e variants were identified in a homozygous (n\u0026thinsp;=\u0026thinsp;45/127, 35.4%), compound heterozygous (n\u0026thinsp;=\u0026thinsp;36/127, 28.3%), 1 digenic (heterozygous for \u003cem\u003eGJB2\u003c/em\u003e combined with the \u003cem\u003eGJB6\u003c/em\u003e del(\u003cem\u003eGJB6\u003c/em\u003e-D13S11830) deletion) and autosomal dominant (n\u0026thinsp;=\u0026thinsp;1) or heterozygous (n\u0026thinsp;=\u0026thinsp;44/127, 34.6%) state. Of the 36 individuals with compound heterozygous variants, 3 had only one of the variants rated as pathogenic. Of the 44 individuals with heterozygous variants, 22 had variants that were pathogenic or likely pathogenic and 22 had variants that were of unknown significance, benign or likely benign. These 47 individuals were included in the demographic analysis but were treated separately in the genotype-phenotype analysis.\u003c/p\u003e\n\u003cp\u003eIn total, only 80 individuals were biallelic for pathogenic/likely pathogenic variants including one heterozygous with autosomal dominant inheritance.\u003c/p\u003e\n\u003cp\u003eThree recurrent variants, c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A p(Val37Ile), c.35delG p.(Gly12Valfs*2), and c.101T\u0026thinsp;\u0026gt;\u0026thinsp;C p.(Met34Thr) accounted for 48.4% (n\u0026thinsp;=\u0026thinsp;77/159), 31.4% (n\u0026thinsp;=\u0026thinsp;50/159) and 15.5% (n\u0026thinsp;=\u0026thinsp;25/159) of all pathogenic or likely pathogenic variant alleles respectively. Furthermore, the c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A variant accounted for the majority of homozygous cases (n\u0026thinsp;=\u0026thinsp;32/45, 71.1%). (See Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eb). Table\u0026nbsp;1 demonstrates the distribution of the variants in the cohort for the 80 individuals with biallelic variants. Details of the remaining 47 individuals are presented in Supplementary Table\u0026nbsp;2.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eGenotypes and phenotypes with age at genetic testing for individuals with biallelic or heterozygous (autosomal dominant) variants in \u003cem\u003eGJB2 \u003c/em\u003eNM_004004.5 (NP_003995.2) n=80\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eZygosity\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge at genetic testing (years)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVariant(s)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInitial HL degree (better ear)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLatest HL degree (better ear)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eACMG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eClinVar\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGnoMAD MAF\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAutosomal\u003c/p\u003e\n\u003cp\u003eDominant\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 5 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.551G\u0026thinsp;\u0026gt;\u0026thinsp;A\u0026nbsp;p.(Arg184Gln)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod-severe\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003esevere\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enot found\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"45\" align=\"left\"\u003e\n\u003cp\u003eHomozygous\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"11\" align=\"left\"\u003e\n\u003cp\u003ec.35delG\u0026nbsp;p.(Gly12Valfs*2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eprofound\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eprofound\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"11\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"11\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"11\" align=\"left\"\u003e\n\u003cp\u003e0.005\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eprofound\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eprofound\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003esevere\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emissing\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emissing\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod-severe\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003esevere\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003esevere\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003esevere\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 6 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod-severe\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod-severe\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 1 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod-severe\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod-severe\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eprofound\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eprofound\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod-severe\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod-severe\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 years, 4 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"32\" align=\"left\"\u003e\n\u003cp\u003ec.109G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Val37Ile)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"32\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"32\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"32\" align=\"left\"\u003e\n\u003cp\u003e0.007\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 years, 8 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 years, 3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 years, 6 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 years, 8 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 years, 1 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emissing\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 years, 11 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 years, 4 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 years, 9 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 8 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod-severe\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 1 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 6 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 years, 11 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 years, 6 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emissing\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 1 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 years, 4 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emissing\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 4 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 8 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 4 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 years, 3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 5 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 4 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 5 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 4 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003ec.101T\u0026thinsp;\u0026gt;\u0026thinsp;C p.(Met34Thr)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emissing\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.008\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"34\" align=\"left\"\u003e\n\u003cp\u003eCompound heterozygous or Digenic (pathogenic variants)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.71G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Trp24*)\u003c/p\u003e\n\u003cp\u003ec.250G\u0026thinsp;\u0026gt;\u0026thinsp;C\u0026nbsp;p.(Val84Leu)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eprofound\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eprofound\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.00002\u003c/p\u003e\n\u003cp\u003e0.00004\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 1 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.71G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Trp24*)\u003c/p\u003e\n\u003cp\u003ec.458_475dup p.(Val153_Tyr158dup)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eprofound\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eprofound\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.00002\u003c/p\u003e\n\u003cp\u003enot reported\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 years, 8 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.101T\u0026thinsp;\u0026gt;\u0026thinsp;C\u0026nbsp;p.(Met34Thr)\u003c/p\u003e\n\u003cp\u003ec.109G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Val37Ile)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.008\u003c/p\u003e\n\u003cp\u003e0.007\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 1 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.101T\u0026thinsp;\u0026gt;\u0026thinsp;C\u0026nbsp;p.(Met34Thr)\u003c/p\u003e\n\u003cp\u003ec.298C\u0026thinsp;\u0026gt;\u0026thinsp;Tp.(His100Tyr)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.008\u003c/p\u003e\n\u003cp\u003e0.00001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 years, 1 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.109G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Val37Ile)\u003c/p\u003e\n\u003cp\u003ec.508_511dup\u0026nbsp;p.(Ala171Glufs*40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.007\u003c/p\u003e\n\u003cp\u003e0.00001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.235delC\u0026nbsp;p.(Leu79Cysfs*3)\u003c/p\u003e\n\u003cp\u003ec.299_300delAT\u0026nbsp;p.(His100Argfs*14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0005\u003c/p\u003e\n\u003cp\u003e0.00006\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 4 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.250G\u0026thinsp;\u0026gt;\u0026thinsp;C\u0026nbsp;p.(Val84Leu)\u003c/p\u003e\n\u003cp\u003ec.-23\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.00004\u003c/p\u003e\n\u003cp\u003e0.0002\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.35delG\u0026nbsp;\u0026nbsp;p.(Gly12Valf*2)\u003c/p\u003e\n\u003cp\u003ec.-23\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emissing\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.005\u003c/p\u003e\n\u003cp\u003e0.0002\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 6 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"11\" align=\"left\"\u003e\n\u003cp\u003ec.35delG\u0026nbsp;\u0026nbsp;p.(Gly12Valf*2)\u003c/p\u003e\n\u003cp\u003ec.101T\u0026thinsp;\u0026gt;\u0026thinsp;C\u0026nbsp;p.(Met34Thr)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"11\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"11\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"11\" align=\"left\"\u003e\n\u003cp\u003e0.005\u003c/p\u003e\n\u003cp\u003e0.008\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 years, 4 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emissing\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 years, 11 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 years, 6 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 years, 5 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emissing\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 years, 7 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emissing\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 years, 8 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003ec.35delG p.(Gly12Valfs*2)\u003c/p\u003e\n\u003cp\u003ec.139G\u0026thinsp;\u0026gt;\u0026thinsp;T p.(Glu47*)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod-severe\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emissing\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.005\u003c/p\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 1 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003esevere\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 years, 10 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003ec.35delG\u0026nbsp;p.(Gly12Valfs*2)\u003c/p\u003e\n\u003cp\u003ec.109G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Val37Ile)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.005\u003c/p\u003e\n\u003cp\u003e0.007\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 6 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 7 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.35delG\u0026nbsp;p.(Gly12Valfs*2)\u003c/p\u003e\n\u003cp\u003ec.313_326del\u0026nbsp;p.(Lys105Glyfs*5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eprofound\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emissing\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.005\u003c/p\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 1 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"4\" align=\"left\"\u003e\n\u003cp\u003ec.35delG\u0026nbsp;p.(Gly12Valfs*2)\u003c/p\u003e\n\u003cp\u003ec.269T\u0026thinsp;\u0026gt;\u0026thinsp;C p.(Leu90Pro)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emissing\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e0.005\u003c/p\u003e\n\u003cp\u003e0.0006\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 1 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emissing\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.35delG\u0026nbsp;p.(Gly12Valfs*2)\u003c/p\u003e\n\u003cp\u003ec.169C\u0026thinsp;\u0026gt;\u0026thinsp;T\u0026nbsp;\u0026nbsp;p.(Gln57*)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.005\u003c/p\u003e\n\u003cp\u003e0.00003\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.35delG\u0026nbsp;p.(Gly12Valf*2)\u003c/p\u003e\n\u003cp\u003ec.235delC\u0026nbsp;\u0026nbsp;p.(Leu79Cysfs*3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod-severe\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emod-severe\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.005\u003c/p\u003e\n\u003cp\u003e0.0005\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.109G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Val37Ile)\u003c/p\u003e\n\u003cp\u003ec.583A\u0026thinsp;\u0026gt;\u0026thinsp;G\u0026nbsp;p.(Met195Val)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eLP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.007\u003c/p\u003e\n\u003cp\u003e0.00003\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.\u0026nbsp;34G\u0026thinsp;\u0026gt;\u0026thinsp;T\u0026nbsp;p.(Gly12Cys)\u003c/p\u003e\n\u003cp\u003ec.109G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Val37Ile)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0005\u003c/p\u003e\n\u003cp\u003e0.007\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 years, 1 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.101T\u0026thinsp;\u0026gt;\u0026thinsp;C\u0026nbsp;p.(Met34Thr)\u003c/p\u003e\n\u003cp\u003ec.194A\u0026thinsp;\u0026gt;\u0026thinsp;G\u0026nbsp;p.(Tyr65Cys)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eLP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eLP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.008\u003c/p\u003e\n\u003cp\u003e0.00001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 years, 2 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.101T\u0026thinsp;\u0026gt;\u0026thinsp;C\u0026nbsp;p.(Met34Thr)\u003c/p\u003e\n\u003cp\u003edel(GJB6-D13S11830)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.008\u003c/p\u003e\n\u003cp\u003enot found\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003cp\u003eA single patient carried del(\u003cem\u003eGJB6\u003c/em\u003e-D13S11830), in conjunction with a \u003cem\u003eGJB2\u003c/em\u003e c.101T\u0026thinsp;\u0026gt;\u0026thinsp;C variant. The autosomal dominant variant, c.551G\u0026thinsp;\u0026gt;\u0026thinsp;A, was identified in a case whose mother also had SNHL and had been previously reported in association with DFNA3.[\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003eBiallelic cases: Hearing profiles\u003c/h2\u003e\n\u003cp\u003eThe specific genotype-phenotype analysis was performed on 80 individuals with biallelic or an autosomal dominant variant. The mean age at testing for this group was 1.8 years with a median age at testing of 4 months. The most frequent loss in the better ear was mild 43/80 (53.8%), with 10/80 initially coded as normal in the better hearing ear (12.5%), 11/80 moderate (13.8%), 7/80 moderately severe (8.8%), 2/80 severe (2.5%) and 6/80 profound (7.5%) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea). For the initial hearing assessments, one patient had missing data, but was included because their subsequent audiogram was available. 60/80 patients had subsequent audiogram data available to evaluate change in hearing over time. Proportions of children in the severity categories was similar between initial and latest assessments. (Supplementary Fig.\u0026nbsp;1). Note that overall hearing was defined by the better hearing ear. 60 of the 80 patients in this group had information about stability and 49 of those had stable hearing profiles (49/60\u0026thinsp;=\u0026thinsp;81.6%) with most having mild hearing loss (n\u0026thinsp;=\u0026thinsp;25/60, 41.6%). Two patients had fluctuating hearing profiles with mild hearing loss on their latest test (n\u0026thinsp;=\u0026thinsp;2/60, 3.3%). Both individuals were homozygous for the c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A variant. The other 9 individuals (n\u0026thinsp;=\u0026thinsp;9/60, 15%) had progressive HL. Further information can be found in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Taba\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cp\u003eTable 2a\u003c/p\u003e\n\u003cp\u003eGenotype-phenotype correlations for progressive hearing loss n=15 (15/127 =11.8% of the cohort)\u003c/p\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eGenotype\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eZygosity\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNumber (%) of children\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDegree of HL initial\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDegree of HL latest\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eHomozygous and compound heterozygous Pathogenic/Likely Pathogenic n\u0026thinsp;=\u0026thinsp;9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.551G\u0026thinsp;\u0026gt;\u0026thinsp;A\u0026nbsp;p.(Arg184Gln)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAutosomal dominant\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emoderately-severe\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003esevere\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.109G\u0026thinsp;\u0026gt;\u0026thinsp;A p(Val37Ile)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehmz\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild (deterioration in low frequencies)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.35delG p.(Gly12Valfs*2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehmz\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emoderately-severe\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003esevere\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.35delG p.(Gly12Valfs*2)\u003c/p\u003e\n\u003cp\u003ec.101T\u0026thinsp;\u0026gt;\u0026thinsp;C\u0026nbsp;p.(Met34Thr)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ecomp het\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 normal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 mild (U-shaped)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.35delG p.(Gly12Valfs*2)\u003c/p\u003e\n\u003cp\u003ec.139G\u0026thinsp;\u0026gt;\u0026thinsp;T\u0026nbsp;\u0026nbsp;p.(Glu47Ter)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ecomp het\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emoderate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003esevere (cochlear implants)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.35delG p.(Gly12Valfs*2)\u003c/p\u003e\n\u003cp\u003ec.269T\u0026thinsp;\u0026gt;\u0026thinsp;C\u0026nbsp;p.(Leu90Pro)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ecomp het\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.109G\u0026thinsp;\u0026gt;\u0026thinsp;A p(Val37Ile)\u003c/p\u003e\n\u003cp\u003ec.508_511dup\u0026nbsp;p.(Ala171Glufs*40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ecomp het\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild (U-shaped)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eHeterozygous (pathogenic/likely pathogenic) n\u0026thinsp;=\u0026thinsp;4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.35delGp.(Gly12Valfs*2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehet\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emoderate\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.101T\u0026thinsp;\u0026gt;\u0026thinsp;C\u0026nbsp;p.(Met34Thr)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehet\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 normal; 1 moderate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 moderately-severe sloping\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.313_326del\u0026nbsp;p.(Lys105Glyfs*5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehet\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eHeterozygous (likely benign/benign) n\u0026thinsp;=\u0026thinsp;2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.-216T\u0026thinsp;\u0026gt;\u0026thinsp;G p.(=)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehet\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emoderate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModerately -severe\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.79G\u0026thinsp;\u0026gt;\u0026thinsp;A\u0026nbsp;p.(Val27Ile)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHet\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003esevere\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eHmz\u0026thinsp;=\u0026thinsp;homozygous; comp het\u0026thinsp;=\u0026thinsp;compound heterozygous\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2b\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eGenotype Phenotype correlations with initial hearing loss coded as \u0026lsquo;normal\u0026rsquo; (n\u0026thinsp;=\u0026thinsp;25 25/127\u0026thinsp;=\u0026thinsp;19.6% of the cohort)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eGenotype\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eZygosity\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNo of children\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDegree of HL initial \u0026lsquo;normal\u0026rsquo;\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDegree of HL latest\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eHomozygous and compound heterozygous (pathogenic/likely pathogenic) n\u0026thinsp;=\u0026thinsp;10\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.109G\u0026thinsp;\u0026gt;\u0026thinsp;A p(Val37Ile)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehmz\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 normal,\u003c/p\u003e\n\u003cp\u003e3 slight,\u003c/p\u003e\n\u003cp\u003e2 unilateral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 unilateral,\u003c/p\u003e\n\u003cp\u003e3 slight\u003c/p\u003e\n\u003cp\u003e1 mild\u003c/p\u003e\n\u003cp\u003e1 missing\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.109G\u0026thinsp;\u0026gt;\u0026thinsp;A p(Val37Ile)\u003c/p\u003e\n\u003cp\u003ec.508_511dup\u0026nbsp;p.(Ala171Glufs*40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ecomp het\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eunilateral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ebilat mild to mod\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35delG p.(Gly12Valfs*2)\u003c/p\u003e\n\u003cp\u003ec.101T\u0026thinsp;\u0026gt;\u0026thinsp;C\u0026nbsp;p.(Met34Thr)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ecomp het\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eunilateral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eProgressed to bilat U-shaped\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35delG p.(Gly12Valfs*2)\u003c/p\u003e\n\u003cp\u003ec.269T\u0026thinsp;\u0026gt;\u0026thinsp;C\u0026nbsp;p.(Leu90Pro)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ecomp het\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ebilat mild rising\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eCompound heterozygous (one pathogenic variant) and heterozygous n\u0026thinsp;=\u0026thinsp;7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.109G\u0026thinsp;\u0026gt;\u0026thinsp;A p(Val37Ile)\u003c/p\u003e\n\u003cp\u003ec.265C\u0026thinsp;\u0026gt;\u0026thinsp;Tp.(Leu89Phe)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehet\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eslight L\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.109G\u0026thinsp;\u0026gt;\u0026thinsp;A p(Val37Ile)\u003c/p\u003e\n\u003cp\u003ec.571T\u0026thinsp;\u0026gt;\u0026thinsp;C\u0026nbsp;p.(Phe191Leu)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehet\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnilateral L high frequency\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eL U-shaped, R rising\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35delG p.(Gly12Valfs*2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehet\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 unilateral,\u003c/p\u003e\n\u003cp\u003e1 slight\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 unilateral,\u003c/p\u003e\n\u003cp\u003e1 missing\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.101T\u0026thinsp;\u0026gt;\u0026thinsp;C p.(Met34Thr)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehet\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emoderately-severe bilateral\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.313_326del\u0026nbsp;p.(Lys105Glyfs*5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehet\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eunilateral high frequency\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ebilateral mild\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.514T\u0026thinsp;\u0026gt;\u0026thinsp;A\u0026nbsp;p.(Trp172Arg)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehet\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eunilateral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eunilateral\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eHeterozygous (VUS/LB/B) n\u0026thinsp;=\u0026thinsp;8\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.79G\u0026thinsp;\u0026gt;\u0026thinsp;A\u0026nbsp;p.(Val27Ile)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehet\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 normal,\u003c/p\u003e\n\u003cp\u003e2 unilateral,\u003c/p\u003e\n\u003cp\u003e1 slight,\u003c/p\u003e\n\u003cp\u003e1 temporary conductive\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 unilateral,\u003c/p\u003e\n\u003cp\u003e1 temporary conductive\u003c/p\u003e\n\u003cp\u003e1 bilateral profound\u003c/p\u003e\n\u003cp\u003e2 missing\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.341A\u0026thinsp;\u0026gt;\u0026thinsp;G\u0026nbsp;\u0026nbsp;p.(Glu114Gly)\u003c/p\u003e\n\u003cp\u003ec.79G\u0026thinsp;\u0026gt;\u0026thinsp;A\u0026nbsp;p.(Val27Ile)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehet\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eunilateral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emissing\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.-45C\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehet\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eunilateral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eunilateral\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ec.-130C\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehet\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003etemporary conductive\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003etemporary conductive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eComp het\u0026thinsp;=\u0026thinsp;compound heterozygous; VUS\u0026thinsp;=\u0026thinsp;variant of uncertain significance; LB\u0026thinsp;=\u0026thinsp;likely benign; B\u0026thinsp;=\u0026thinsp;benign\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eTen of 80 (12.5%) patients demonstrated hearing that was coded as \u0026lsquo;normal\u0026rsquo; in the better hearing ear at their initial hearing test. The genotype and further information about HL in these individuals is presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb. The majority of these individuals had progression of their HL.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003eHeterozygous cases: Hearing profiles\u003c/h2\u003e\n\u003cp\u003eThe hearing profiles in heterozygous cases can be seen in Supplementary Table\u0026nbsp;2, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea and Supplementary Fig.\u0026nbsp;1b. Of the 47 individuals with heterozygous variants and those with variants of uncertain significance or likely benign, the hearing profiles were similar between the initial and latest assessment with nine not having follow up audiogram data. The proportions of HL severity at the initial time point were 15/47 (31.9%) normal in the better ear (more detail in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e) mild 21/47 (44.7%), moderate 8/47 (17%) and one each of moderately-severe (2.1%), severe (2.1%) and profound (2.1%) (Supplementary Fig.\u0026nbsp;1b).\u003c/p\u003e\n\u003cp\u003eHL progression was assessable in 97 individuals (from both biallelic and heterozygous groups) who had audiograms at multiple time points and sufficient information to code HL stability. Progressive HL was seen in 15 total; 9/60 (15%) in the homozygous/compound heterozygous/AD group and 6/37 (16.2%) in the heterozygous/VUS/likely benign group. Genotypes of those individuals are presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea and include the autosomal dominant variant, homozygous and compound heterozygous c.35delG and c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A as well as several other genotypes.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n\u003ch2\u003eBiallelic Cases: Genotype-Phenotype Associations\u003c/h2\u003e\n\u003cp\u003eThe three most common variants had sufficient sample size for Pearson\u0026rsquo;s chi-squared or Fisher\u0026rsquo;s exact statistical test analysis for association between genotype and phenotypic characteristics and were all present in homozygous, compound heterozygous and heterozygous states (More detail in Table\u0026nbsp;1). Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea demonstrates the degree of initial HL by zygosity and 1b demonstrates the degree of initial HL for the three most frequent variants in homozygous state. The most frequent variant, c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A, had sufficient numbers for analysis for phenotypic associations with both homozygous state and combination of homozygous/compound heterozygous, and c.35delG and c.101T\u0026thinsp;\u0026gt;\u0026thinsp;C had sufficient numbers for this analysis of homozygous/compound heterozygous state.\u003c/p\u003e\n\u003cp\u003eFisher exact statistical test analysis found that patients who were homozygous for c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A were much more likely to have mild hearing loss and less moderately severe/severe/profound for both their initial and latest hearing tests (p\u0026thinsp;=\u0026thinsp;0.0004 and 0.006 respectively) than the rest of the cohort. Individuals who were homozygous/compound heterozygous for the c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A variant were also significantly more likely to have mild hearing loss (versus moderately-severe/severe/profound hearing loss) as compared to those not carrying the c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A variant for both the initial (p\u0026thinsp;=\u0026thinsp;0.00004) and most recent audiogram data (p\u0026thinsp;=\u0026thinsp;0.0004) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eDegree of HL initial and latest for patients (i) homozygous for \u003cem\u003eGJB2\u003c/em\u003e c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Val37Ile), (ii) homozygous or compound heterozygous c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Val37Ile) and (iii) homozygous or compound heterozygous c.35delG p(Gly12Valfs*2) variant present (Fisher\u0026rsquo;s exact statistical test)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"6\" align=\"left\"\u003e\n\u003cp\u003ec. 109G\u0026thinsp;\u0026gt;\u0026thinsp;A hmz/comp het versus heterozygous or negative\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003ec.35delG hmz/comp het versus heterozygous/negative cases\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHomozygous c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A variant\u003c/strong\u003e (\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;32\u003c/strong\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003enegative, comp het or het for c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(N\u0026thinsp;=\u0026thinsp;48\u003c/strong\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ep-value*\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAll Hmz and comp het c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(N\u0026thinsp;=\u0026thinsp;38\u003c/strong\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNegative or het for c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;42\u003c/strong\u003e \u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ep-value*\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHmz or comp het c.35delG\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(N\u0026thinsp;=\u0026thinsp;34\u003c/strong\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003enegative or het for c.35delG\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(N\u0026thinsp;=\u0026thinsp;46\u003c/strong\u003e \u003csup\u003e\u0026dagger;\u003c/sup\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ep-value*\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDegree of Hearing Loss- Initial\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.0004\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.00004\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.007\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (19%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (8.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (18.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (7.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (9.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (15.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (71%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21 (43.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26 (70.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (40.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (39.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 (65.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModerate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (9.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (16.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (10.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (16.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (15.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (13%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMod- Severe/Severe/Profound\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (31.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (35.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (36.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (6.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnknown\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDegree of Hearing Loss- Latest\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.006\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.0004\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.007\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (13.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (8.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (16.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (3.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (16.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23 (76.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26 (72.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (41.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (47.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27 (64.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModerate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (6.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (20%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (8.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (20.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (17.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (11.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModerately- Severe/Severe/Profound\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (3.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (28.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (2.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (34.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (34.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (7.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnknown\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"10\"\u003e* Fisher\u0026rsquo;s exact probability test\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eIndividuals who were homozygous/compound heterozygous for the c.35delG variant had significantly more moderately-severe/severe/profound hearing loss than those with other genotypes at both time points (p\u0026thinsp;=\u0026thinsp;0.007 and 0.007 respectively) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eIndividuals who were homozygous/compound heterozygous for the c.101T\u0026thinsp;\u0026gt;\u0026thinsp;C variant had significantly more U-shaped and sloping audiograms than other audiogram configurations at the most recent time point (p\u0026thinsp;=\u0026thinsp;0.02) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). There were no other significant associations between genotype and any of the other audiology descriptors (audiogram shape, symmetry or stability).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eAudiogram shape initial and latest for patients: c.101T\u0026thinsp;\u0026gt;\u0026thinsp;C p(Met34Thr) homozygous/compound heterozygous variant present (Fisher\u0026rsquo;s exact statistical test)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCharacteristic\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eHmz/comp het c.101T\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e\n\u003cp\u003ePresent: N\u0026thinsp;=\u0026thinsp;17\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003enegative or het for c.101T\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e\n\u003cp\u003eN\u0026thinsp;=\u0026thinsp;63\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep-value*\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAudiogram shape- initial\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.14\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFlat\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (43.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e39 (61.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRising\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (7.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSloping\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (43.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (27%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eU-shaped\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (12.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (3.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnknown\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAudiogram shape- Latest\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFlat\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (21.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26 (53.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRising\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (8.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSloping\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (42.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (30.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eU-shaped\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (35.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (8.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnknown\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003e* Fisher exact probability test\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n\u003ch2\u003eGenotype-Phenotype association: progressive HL and \u0026lsquo;normal\u0026rsquo; hearing\u003c/h2\u003e\n\u003cp\u003eOf the 10 individuals who were homozygous/compound heterozygous who had normal hearing in the better ear on the initial audiogram (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb), 6 were homozygous for c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A. There were 2 individuals who were compound heterozygous for c.35delG/c.101T\u0026thinsp;\u0026gt;\u0026thinsp;C who had unilateral HL at the initial time point and bilateral U-shaped HL at the most recent time point. Six of the 15 individuals with progressive HL (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea) had at least one variant that was c.35delG.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study reports variant data from a geographical region which has been understudied to date. State-wide newborn screening (99% coverage), and follow-up \u003cem\u003eGJB2/6\u003c/em\u003e testing in screen positive individuals revealed biallelic and heterozygous carriage in association with predominantly mild hearing loss. The most frequent variant, c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A, has been described with mild phenotypes, and may partially explain the increase in mild hearing loss detected on newborn screening. Consistent with the literature, the c.35delG variant was associated with more severe HL, while the c.101T\u0026thinsp;\u0026gt;\u0026thinsp;C variant was associated with milder HL and U-shaped audiograms. This information provides a more complete picture of the phenotypic spectrum of \u003cem\u003eGJB2/6\u003c/em\u003e associated HL which provides short-term prognostic data and can inform pre- and post-natal counselling for individuals and families found to carry these variants.\u003c/p\u003e \u003cp\u003eAscertainment in this study differs from most previously reported literature which genetically evaluated individuals being considered for cochlear implants i.e., typically severe levels of hearing loss [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In those studies, the most common variants were c.35delG and c.235delC which were identified in populations from European and Asian backgrounds, respectively. The c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A variant has been reported previously, especially from Asian ancestry cohorts [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], where the minor allele frequency is 0.08 [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Thus, it is unsurprising that it is prevalent in our agnostically ascertained cohort where the sensitive equipment used for universal newborn hearing screening and aABR (automated auditory evoked brainstem response) as a screening method can lead to capturing patients that may have mild, transient and/or fluctuating hearing profiles.\u003c/p\u003e \u003cp\u003eAn artefact of newborn screening is the detection of mild hearing loss. As mild hearing-loss is being increasingly diagnosed at an earlier age [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], this presents prognostic and management uncertainty for both families [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] and clinicians [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. This study provides evidence for a genetic basis for many mild hearing loss cases adding to the emerging body of literature describing genotypes in mild and moderate hearing loss cohorts [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrior publications have noted milder hearing loss in association with either c.101T\u0026thinsp;\u0026gt;\u0026thinsp;C or c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A alleles [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. The pathogenic classifications of both variants were initially controversial, but an international consensus paper classified both as pathogenic with variable expressivity and incomplete penetrance [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Consistently, in this Australian cohort this variant is associated with a milder phenotype. This phenotypic information is valuable for clinicians and families presented with these results in infancy, prenatally or as part of reproductive carrier screening [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevious research has shown that a heterozygous \u003cem\u003eGJB2\u003c/em\u003e variant is detected in 10\u0026ndash;50% of individuals with hearing loss [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], which can complicate and limit clinical interpretation and management. Additionally, some studies have indicated that carriers of certain variants have been reported to be more likely than \u0026lsquo;non-carriers\u0026rsquo; to develop hearing impairment when exposed to other environmental factors or genetic defects [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. In the current study, heterozygosity was identified in 37% of the cohort and the associated hearing loss phenotype was highly variable ranging from normal (in the better ear) to profound. These findings align with previous publications [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] and may be due to (i) the \u003cem\u003eGJB2\u003c/em\u003e variant being coincidental, with hearing loss secondary to variants in another NSHL gene, (ii) failure to detect a second, possibly intronic functionally significant variant in \u003cem\u003eGJB2\u003c/em\u003e, (iii) the \u003cem\u003eGJB2\u003c/em\u003e variant modifies the expression of other variants in related hearing loss genes or (iv) the \u003cem\u003eGJB2\u003c/em\u003e variant being coincidental and the hearing loss stemming from a non-genetic aetiology. Comprehensive panel testing and/or whole genome sequencing may help identify the first two possibilities [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], and further research could possibly elucidate the third.\u003c/p\u003e \u003cp\u003eIt is important to appreciate that classification of hearing loss in this study is relative to the better hearing ear. Thus, our study detected individuals with normal hearing and asymmetric hearing loss where the hearing of the contralateral ear could range from mild to profound. The fact that genetic testing was offered in these cases implies that the hearing loss was, at the time of testing, considered to be clinically indicated and/or socially significant to the individual or their families. While hearing loss in some cases may have been complicated by transient, conductive overlay, the findings from the present study support that \u003cem\u003eGJB\u003c/em\u003e2 variants can be associated with asymmetric hearing loss [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The identification of these asymmetric cases (where one ear is classified as \u0026lsquo;normal\u0026rsquo; hearing) may be reduced from this point forward given recommendations to only offer genetic testing in cases of bilateral hearing loss [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. However, a uniform and consistent approach to genetic testing for patients with NSHL is important to mitigate the risk of uncertain findings. Furthermore, this could potentially reduce the financial and psychological costs associated with inappropriate genetic testing.\u003c/p\u003e \u003cp\u003eThe natural history in this cohort was predominantly stable but shows both improvements and progression over time. These findings are consistent with those previously reported in the literature [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. However, it should be noted that audiogram results become more accurate with increasing age in children, thus fluctuation/progression may reflect the young age of this cohort. Importantly, U-shaped hearing loss was identified more frequently at subsequent time points than initial assessments and was associated with c.101T\u0026thinsp;\u0026gt;\u0026thinsp;C. There is a paucity of literature on U-shaped (mid-frequency) hearing loss, an uncommon audiometric finding, more commonly diagnosed in older individuals [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Although U-Shaped hearing loss has not been formally associated with \u003cem\u003eGJB2\u003c/em\u003e generally and the c.101T\u0026thinsp;\u0026gt;\u0026thinsp;C variant specifically, in reviewing previously published audiograms in c.101T\u0026thinsp;\u0026gt;\u0026thinsp;C positive individuals [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e], we identified cases of U-Shaped hearing loss. This is clinically significant because this mid-frequency loss is associated with greater difficulty understanding speech in a noisy environment such as a classroom setting. Thus, children may function differentially in quiet and noisy environments, which could mask detection, thus increasing the risk of social problems and fatigue, especially if it is a deterioration [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCumulatively, these results demonstrate a broad phenotypic association with \u003cem\u003eGJB2\u003c/em\u003e variants and some genotype-phenotype associations which can provide prognostic value. This data from a population wide cohort, provides prognostic information for preconception, prenatal and paediatric counselling of couples and families carrying these variants. For example, Freeman et al.\u0026rsquo;s [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e] discussion of views regarding genetic testing for deafness in reproductive settings, highlighted that the recent American College of Medical Genetics and Genomics practice guidelines [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] recommended the inclusion of \u003cem\u003eGJB2\u003c/em\u003e variants in prenatal genetic screening on the basis of prevalence and NSHL being categorised as \u0026lsquo;moderately severe\u0026rsquo; [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. If such guidelines were adopted in Australia, the information in studies like this would be invaluable in counselling.\u003c/p\u003e \u003cp\u003eStrengths of this study include the agnostic mode of ascertainment which allowed for identification of a broad phenotypic spectrum. The centralisation of newborn screening, pathology and clinical data allowed for comprehensive phenotypic characterisation. Limitations include a finite sample size and follow up period, lack of detailed data about other potentially contributing factors for HL and the fact that testing was limited to \u003cem\u003eGJB2\u003c/em\u003e coding variants and a single \u003cem\u003eGJB6\u003c/em\u003e deletion.\u003c/p\u003e \u003cp\u003eFuture directions to further assist clinicians in providing genetic counselling in this area could include longer follow-up to clarify stability over time, broadening the phenotype to include developmental outcomes including speech and language development and response to intervention e.g., documenting outcomes of children who have required cochlear implants, and comprehensive panel testing for hearing loss. Cumulatively, this information would provide clinicians and families with greater prognostic and management certainty at the time of diagnosis.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study provides valuable insights for managing and counselling individuals with \u003cem\u003eGJB2/GJB6\u003c/em\u003e variants. The phenotypic spectrum in biallelic individuals in this cohort is milder than has been previously reported, likely due to the agnostic ascertainment. Conversely, our study identified a portion of heterozygous carriers experienced hearing loss, which ranged from mild to moderate. The publication of the full spectrum of presentations offsets the prior publication of more severe presentations, which has potentially skewed the overall perception of the severity of the condition. Given the increasing interest in pre-conception carrier testing for deafness, larger cohort data is crucial to provide personalised, accurate genetic counselling.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eConflict of Interest\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grants from funding agencies in the public, commercial or not-for profit sectors.\u003c/p\u003e\n\u003cp\u003eData Availability Statement\u003c/p\u003e\n\u003cp\u003eThe data are available in Table 1 and Supplementary Table 2 and the variants have been submitted to ClinVar SUB13514054.\u003c/p\u003e\n\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eRK: literature review, extracted, collated and cleaned data, performed descriptive statistics, drafted initial manuscript and edited revisions\u003c/p\u003e\n\u003cp\u003eRB: provided advice on design and development of study, reviewed and revised manuscript\u003c/p\u003e\n\u003cp\u003eMTG: curated variant impact, reviewed and revised manuscript\u003c/p\u003e\n\u003cp\u003eAML: supervised variant analysis, revised and edited drafts\u003c/p\u003e\n\u003cp\u003eCD: edited the draft\u003c/p\u003e\n\u003cp\u003eKL: conceptualised and designed the study, extracted clinical data, performed descriptive statistics, reviewed and revised manuscript\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eThe authors would like to acknowledge Ben Lundie, Chiyan Lau for help extracting genetic data, Megan Moore and Jane Fitzgibbons for help extracting audiological data and Ella McGahan for help with formatting and proof reading\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRouse, S.L., et al., \u003cem\u003eRacial and ethnic disparities in genetic testing for hearing loss: a systematic review and synthesis.\u003c/em\u003e Hum Genet, 2022. \u003cstrong\u003e141\u003c/strong\u003e(3-4): p. 485-494.\u003c/li\u003e\n\u003cli\u003eWorld Health Organisation., \u003cem\u003eWorld report on hearing\u003c/em\u003e. 2021: Geneva.\u003c/li\u003e\n\u003cli\u003eBrewer, C.C. and K.A. 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Del Castillo, \u003cem\u003eDFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes.\u003c/em\u003e Front Mol Neurosci, 2017. \u003cstrong\u003e10\u003c/strong\u003e: p. 428.\u003c/li\u003e\n\u003cli\u003eBirkenbeuel, J., et al., \u003cem\u003eCharacteristics of Mid-Frequency Sensorineural Hearing Loss Progression.\u003c/em\u003e Otol Neurotol, 2019. \u003cstrong\u003e40\u003c/strong\u003e(5): p. e497-e502.\u003c/li\u003e\n\u003cli\u003eSnoeckx, R.L., et al., \u003cem\u003eGJB2 mutations and degree of hearing loss: a multicenter study.\u003c/em\u003e Am J Hum Genet, 2005. \u003cstrong\u003e77\u003c/strong\u003e(6): p. 945-57.\u003c/li\u003e\n\u003cli\u003eTharpe, A.M. and R. Seewald, \u003cem\u003eComprehensive Handbook of Pediatric Audiology\u003c/em\u003e. 2016, San Diego, UNITED STATES: Plural Publishing, Inc.\u003c/li\u003e\n\u003cli\u003eFreeman, L., et al., \u003cem\u003eThe views of people with a lived experience of deafness and the general public regarding genetic testing for deafness in the reproductive setting: A systematic review.\u003c/em\u003e Genet Med, 2022. \u003cstrong\u003e24\u003c/strong\u003e(9): p. 1803-1813.\u003c/li\u003e\n\u003cli\u003eLazarin, G.A., et al., \u003cem\u003eSystematic Classification of Disease Severity for Evaluation of Expanded Carrier Screening Panels.\u003c/em\u003e PLoS One, 2014. \u003cstrong\u003e9\u003c/strong\u003e(12): p. e114391.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-human-genetics","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ejhg","sideBox":"Learn more about [European Journal of Human Genetics](http://www.nature.com/ejhg/)","snPcode":"41431","submissionUrl":"https://mts-ejhg.nature.com/cgi-bin/main.plex","title":"European Journal of Human Genetics","twitterHandle":"@ejhg_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"GJB2, GJB6, Connexin 26, Hearing loss, genotype-phenotype, paediatric, deafness","lastPublishedDoi":"10.21203/rs.3.rs-3829481/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3829481/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGuidelines recommend \u003cem\u003eGJB2\u003c/em\u003e (connexin 26) and \u003cem\u003eGJB6\u003c/em\u003e (connexin 30) testing for bilateral non-syndromic sensorineural hearing loss (SNHL). However, associated audiological phenotypes vary. There is limited Australian data on \u003cem\u003eGJB2\u003c/em\u003e variant frequency and associated phenotypes. Audiograms from a paediatric cohort with SNHL, predominantly identified through newborn hearing screening and carrying \u003cem\u003eGJB2\u003c/em\u003e variants and/or a \u003cem\u003eGJB6\u003c/em\u003e deletion (\u003cem\u003eGJB6\u003c/em\u003e-D13S11830) were retrospectively reviewed (n\u0026thinsp;=\u0026thinsp;127). Two thirds were homozygous or compound heterozygous for pathogenic or likely pathogenic variants of \u003cem\u003eGJB2\u003c/em\u003e and/or \u003cem\u003eGJB6\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;80). The most frequent variant, c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A, occurred in homozygous (n\u0026thinsp;=\u0026thinsp;32), compound heterozygous (n\u0026thinsp;=\u0026thinsp;8) and heterozygous (n\u0026thinsp;=\u0026thinsp;5) states. Compared to homozygous/compound heterozygous carriage of other \u003cem\u003eGJB2\u003c/em\u003e variants, c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A positive individuals (homozygous/compound heterozygous) were more likely to have mild HL at their initial (p\u0026thinsp;=\u0026thinsp;0.00004) and latest audiograms (p\u0026thinsp;=\u0026thinsp;0.0004). Homozygous/compound heterozygous carriage of c.35delG was associated with moderately-severe or greater HL at both initial (p\u0026thinsp;=\u0026thinsp;0.007) and latest (p\u0026thinsp;=\u0026thinsp;0.007) audiograms. The c.101T\u0026thinsp;\u0026gt;\u0026thinsp;C variant presented with milder HL and U-shaped audiograms (p\u0026thinsp;=\u0026thinsp;0.02). In this agnostically identified cohort, mild HL predominated in \u003cem\u003eGJB2/GJB6\u003c/em\u003e carriers in contrast to previous studies targeting individuals with significant loss. Consequently, c.109G\u0026thinsp;\u0026gt;\u0026thinsp;A, associated with milder phenotypes, was the most frequent. This data provides valuable, balanced prognostic information for preconception, prenatal and paediatric counselling of couples and families carrying these variants.\u003c/p\u003e","manuscriptTitle":"The congenital hearing phenotype in GJB2 in Queensland, Australia: V37I and mild hearing loss predominates","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-17 16:06:27","doi":"10.21203/rs.3.rs-3829481/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-01-30T21:59:56+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-01-25T05:32:17+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-01-23T09:01:31+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-01-18T23:11:15+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-01-17T08:11:04+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-01-15T17:57:08+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-01-15T13:35:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Human Genetics","date":"2024-01-13T02:43:12+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2024-01-11T13:50:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-02T12:18:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-human-genetics","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ejhg","sideBox":"Learn more about [European Journal of Human Genetics](http://www.nature.com/ejhg/)","snPcode":"41431","submissionUrl":"https://mts-ejhg.nature.com/cgi-bin/main.plex","title":"European Journal of Human Genetics","twitterHandle":"@ejhg_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4b623e98-3fae-4493-977e-b86ea6e19c44","owner":[],"postedDate":"January 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":28153966,"name":"Health sciences/Medical research/Genetics research"},{"id":28153967,"name":"Health sciences/Health care/Paediatrics"},{"id":28153968,"name":"Biological sciences/Genetics/Clinical genetics/Genetic testing"},{"id":28153969,"name":"Biological sciences/Genetics/Medical genetics/Genetic counselling"}],"tags":[],"updatedAt":"2024-02-27T15:26:49+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-17 16:06:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3829481","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3829481","identity":"rs-3829481","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}