Post-Genomic Era: Critical Role of Genetic Counseling in a Pediatric Clinic

Post-Genomic Era: Critical Role of Genetic Counseling in a Pediatric Clinic | 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 Research Article Post-Genomic Era: Critical Role of Genetic Counseling in a Pediatric Clinic Brinda Ramanathan, Sunita Mohan, Deepika Karthik Kumar, Sugirdhana Parthiban Ramsait, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7063331/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Establishing a confirmed diagnosis of pediatric-onset genetic conditions has undergone a paradigm shift in the post-genomic era. Consequently, the practice of genetic counseling has also transformed. Clinical and genetic heterogeneities (in monogenic and complex diseases) and variants of uncertain significance (VUS) pose challenges across clinical disciplines. We thus retrospectively analyzed 38 subjects with pediatric-onset conditions who underwent clinical examination, genetic counseling, and testing. The subjects were categorized based on their clinical presentations and genomic screening results (ophthalmic, neurodevelopmental disorders [NDDs], and other pediatric conditions outside the two subspecialties). Among the ophthalmic subjects, 84.6% had confirmed pathogenic/likely pathogenic (P/LP) variants, 7.7% had combinations of P/LP variants and VUS, and 7.7% had no significant molecular genetic variants. In the NDDs group, 44.4% had confirmed P/LP variants, 11.2% had combinations of P/LP variants and VUS, and 44.4% had either only VUSs or uninformative results. In the remaining subjects, 43% carried confirmed (P/LP) variants, 28.5% had a combination of P/LP and VUS, and 28.5% were inconclusive. We discuss the implications of these findings with the subject families and how pre- and post-test genetic counseling aided their informed decision-making. Clinical and genetic heterogeneities present challenges that clinicians and genetic counselors face, differing between monogenic and complex conditions. Genetic counselors should inform patient families of possible outcomes during pre-test and post-test counseling, as it supports informed decision-making. Although VUSs remain the most significant genetic counseling challenge in all three groups, post-genomic era high-throughput technologies have greatly enhanced healthcare delivery. genetic counseling variant of uncertain significance genetic testing clinical genetics pediatric genetic disorders Figures Figure 1 Introduction Many pediatric-onset diseases and congenital anomalies have a genetic etiology (Lee, 2023, McCandless et al., 2004). Advances in genetic testing, such as next-generation sequencing (NGS), have improved healthcare by facilitating accurate diagnosis and genetic counseling of rare pediatric disorders (Nguengang Wakap et al., 2020). Close to 70% of rare genetic disorders occur in childhood, with an average of 4.8 years taken for a definite diagnosis (The Lancet Global, 2024). Genetic diagnoses have various implications. It is a means of closure to diagnostic odysseys (Michaels-Igbokwe et al., 2021) and helps families understand their child’s medical and genetic issues. For healthcare providers, a definite diagnosis aids in the prognosis, direct management, and rehabilitation referrals in setting realistic expectations for the future, including preparing for to-emerge comorbidities (Lalonde et al., 2020, Robin, 2006, Hong et al., 2019). Identifying the genetic cause of pediatric-onset conditions can improve clinical outcomes (Stark et al., 2016b), reduce diagnostic costs (Dragojlovic et al., 2018), and help parents make informed reproductive choices (Elliott, 2020). In the past, diagnostic processes addressed common chromosomal aberrations and monogenic disorders with accompanying laboratory tests that interrogated genes preselected on clinical symptoms or, for example, on biochemical investigations ( 12 ). However, this approach has evolved in the post-genomic era to a gene-first strategy, where targeted gene panels, whole exome or whole genome sequencing, or chromosomal microarray is performed as the first step in the diagnostic process. Genetic counseling, by definition of the National Society of Genetic Counselor’s Task Force report, is the process of helping people to understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease and enable them to make informed decisions (Resta et al., 2006). A genetic counselor’s role transcends the stages of establishing a diagnosis and continues to support families via multidisciplinary teams involving the clinician, laboratory analysts, and other rehabilitation therapists as necessary. Additionally, in this post-genomic era, where genomic tests are performed for monogenic and multifactorial disorders (Couser et al., 2021, Morad et al., 2007, Aldharman et al., 2023, McGlynn and Langfelder-Schwind, 2020), genetic counselors have to educate patient families about the possible outcomes of genomic tests (confirmed or negative for genomic variants, variants of uncertain significance [VUS], secondary or incidental findings) during pre-test genetic counseling (Federici and Soddu, 2020), as this may impact the establishment of an accurate diagnosis, subsequent management, and reproductive options for the patients and parents (Elliott, 2020). Pediatric-onset conditions show wide clinical and genetic heterogeneity. They can be monogenic, like in retinitis pigmentosa (RP) and cystic fibrosis, or, as in pediatric neurodevelopmental disorders (NDDs), be monogenic or complex with multiple genes and environmental factors interfacing (Zschocke et al., 2023, Verma et al., 2018, Carter et al., 2023a, 2024). There are 300 + genes responsible for monogenic inherited retinal degenerative disorders (Holanda et al., 2024) with an estimated prevalence of 1 in 2000 persons, and it affects close to two million people worldwide (Lam et al., 2021). Precise diagnosis is challenging due to the extensive clinical heterogeneity, but advances in DNA sequencing technology have made it easier to find the genetic cause, as they are generally monogenic. The gene-first approach pays off. For instance, retinitis pigmentosa (RP) may overlap with clinical symptoms of Leber congenital amaurosis or cone-rod dystrophy(Chung and Traboulsi, 2009, Moore, 1992) or be associated with non-syndromic and syndromic forms (ciliopathies, mitochondrial disorders, etc. (Fuster-García et al., 2021)), and this difference in diagnosis can be cleared with molecular genetic testing. NDDs such as autism spectrum disorder (ASD), global developmental delay (GDD), attention deficit hyperactivity disorder (ADHD), and intellectual disability (ID), diagnosed as per the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) (Hamanaka et al., 2022, Hu et al., 2014, Association, 2013) affect more than 3% of children worldwide (Parenti et al., 2020) with 1 in 36 children diagnosed with autism alone (Zablotsky et al., 2019, Prevention, 2023). In addition, they exhibit wide phenotypic and genetic heterogeneity (Choi et al., 2021, Bosch et al., 2023, Arnett and Flaherty, 2022, Márquez-Caraveo et al., 2021). Genetic testing for NDDs is tiered and directed by established guidelines owing to their complex etiology (Miller et al., 2010, Srivastava et al., 2019). Close to 40% of NDDs have documented monogenic causes, detected through exome sequencing (2017), and 9–13% have copy number variants (Lee and Nelson, 2020). This leaves a majority genetically uncharacterised and attributable to multifactorial and oligogenic causes or Mendelian genes that are yet to be identified. Other pediatric-onset genetic disorders in disciplines such as neurology, orthopedics, endocrinology, and pulmonology involving conditions such as inborn errors of metabolism, sensorineural hearing loss, mitochondrial disorders, avascular necrosis, etc., also have genomic variations ranging from copy number variations to monogenic sequence changes (Lalonde et al., 2020, Stein et al., 2018). Variants identified through genomic testing are classified according to ACMG/AMP guidelines as pathogenic, likely pathogenic, VUS, likely benign, or benign (Richards et al., 2015). NGS, globally, has no doubt improved diagnostic accuracy and enabled personalized treatment and prevention. However, genomic investigations returning with VUSs or uninformative results are a possibility, whether the condition is monogenic or multifactorial, and add a layer of complexity to genetic counseling in pediatrics (Ramos, 2020, Stewart, 2018, Thomassen Hammerstad et al., 2020, Federici and Soddu, 2020, Hoffman-Andrews, 2017), both in developed (Dwarte et al., 2019) and low- and middle-income countries such as India (Tekola-Ayele and Rotimi, 2015). These results can often be misinterpreted by healthcare professionals and patients, leading to unnecessary interventions and psychological stress for patients and families (Donohue et al., 2021). Informing on secondary and clinically actionable incidental findings unrelated to the primary indication is important to prepare them for such possibilities. Genetic counselors in pediatric clinics, hence, play a critical role in the interpretation of results and guidance of families, reiterating the importance of pre- and post-test genetic counseling (Diderich KEM, 2023, Michaela Cormack, 2024). Post-genomic era genetic counseling challenges need to be addressed within a framework (Stewart, 2018), mindful of the clinical and personal indications of the patients (McGlynn and Langfelder-Schwind, 2020, Menke et al., 2021). This paper focuses on patient groups with ophthalmic, neurodevelopmental, and other pediatric-onset conditions, highlighting their pre- and post-test genetic counseling. Methods We retrospectively studied subjects with pediatric-onset conditions referred to us for genetic counseling between January 2018 and June 2024 at our clinics in GenVams Trust, Chennai, and Nishta Integrated Neurodevelopment Centre, Chennai, India. The subjects were categorized into 3 groups based on the pediatric subspecialty referrals: pediatric-onset ophthalmic concerns, NDDs, and other pediatric referrals that did not belong to the previous two subspecialties. Three-generation pedigrees and detailed clinical and family medical histories were ascertained. Non-directive pre-test genetic counseling addressed genomic testing as per the clinical indication (Savatt and Myers, 2021) (Bateman and Silva, 2013) (Ewans et al., 2018), diagnostic outcomes (detection of a causative variant, VUS, or uninformative results), management, options of estimation of recurrence for future pregnancies in the event of a confirmed genetic diagnosis, the possibility of secondary and clinically actionable incidental findings, and scope of detection of genomic variations in the tests opted for. We explained that in the absence of any genomic variant or detection of uncertain variants, additional tests could be considered, if applicable, as functional assays to assess VUS are not always possible or feasible in a diagnostic lab (Miranda Durkie, 2024). Ophthalmic investigations comprised electroretinography (ERG), optical coherence tomography (OCT), fundus imaging, visual field test, and best corrected visual acuity (BCVA), as verified by the referring ophthalmologists (SM). Subjects with NDDs and other pediatric concerns underwent neurodevelopmental assessments by developmental paediatrician and neonatologists (SS and MJ) and metabolic (enzyme analysis using tandem mass spectroscopy and gas chromatography), haematological, and imaging studies per the individual requirements. Genetic testing was outsourced to genomics laboratories that are CLIA (Clinical Laboratory Improvement Amendments) compliant, and CAP (College of American Pathologists) accredited. This comprised of karyotyping (G-banding at 450 band resolution), NGS-based whole exome sequencing (WES), clinical exome sequencing (CES, sequencing of approximately 8000 genes curated for commonly prevalent clinical genetic conditions) (Campbell et al., 2023), or multi-gene panels (list of genes provided in supplementary data), chromosomal microarray (CMA), multiplex ligation dependant probe amplification (MLPA), and fragile-X syndrome TP-PCR analysis, as specified in Table 2 . Parental testing used the Sanger sequencing method when performed in cases of suspected compound heterozygosity for autosomal recessive (AR) variants. The choice of genomic tests was dependent on the autonomy of the affected family and, particularly, their socioeconomic status. Based on the genomic results with variants classified as per the ACMG criteria (Richards et al., 2015) the subjects were further categorised into three groups: (i) those with a confirmed genetic diagnosis with pathogenic (P) or likely pathogenic (LP) variants, (ii) those with a combination of P/LP variants with VUS, and (iii) those who had only VUSs or nil variants reported. Post-test genetic counseling was focused on interpreting the genetic results following the indication for referral. Clinical details were cross-checked by the clinicians against the identified variant, and possibilities to continue additional testing (clinical and genetic), if indicated, were discussed with the families. Table 1: Distribution of subjects according to their clinical presentation and genetic test results Total N=38 Ophthalmology group (N=13) NDD group (N=18) Other pediatric group (N=7) Only P/LP N=11 (84.6%) N=8 (44.4%) N=3 (43%) Subjects:9,10,11,12,13,14,15,18,19, 24,26 Subjects: 1,3, 4,5, 8,17, 29, 38 Subjects: 2, 6, 16 P/LP with VUS N=1 (7.7%) N=2 (11.2%) N=2 (28.5%) Subjects: 25 Subjects: 22, 23 Subjects: 20, 21 Only VUS/ no genetic result N=1 (7.7%) N=8 (44.4%) N=2 (28.5%) Subjects: 37 Subjects: 7, 28, 30, 31, 32, 34, 35, 36 Subjects: 27, 33 Legend: N-number of subjects, P-pathogenic, LP-Likely pathogenic, VUS-variant of uncertain significance, NDD- NDD-neurodevelopmental disorder Table 2 Demographic, clinical, and molecular genetic details of the subjects Subject Age at referral/ Gender Parental Consanguinity/ Endogamy Clinical indication Genetic test Gene/ Chromosome Variant Zygosity / Inheritance pattern of the reported gene Diagnosis Prediction tools results Laboratory reported classification as per ACMG criteria Subject 1 1year 8months /Male (deceased) Endogamous Congestive hepatomegaly, pallor, congenital hypertrichosis, microcytic hypochromic anemia, pulmonary hypertension, mild cardiomegaly, developmental delay CES ABCC9 c.3461G > A p.Arg1154Gln Heterozygous/ AD Cantu syndrome Damaging (SIFT, LRT, MutationTaster2), Probably damaging (Polyphen-2) Likely pathogenic Subject 2 1 month/ Female Endogamous Newborn screen positive for Immunoreactive trypsinogen CES CFTR c.327T > A p.Tyr109Ter c.3353C > T p.Ser1118Phe Compound heterozygous/ AR Cystic fibrosis Damaging (SIFT, LRT, MutationTaster2), Probably damaging (Polyphen-2) Pathogenic Subject 3 5 years/ Male Endogamous Global developmental delay WES CMA Chr. 5 5p15.33p13.3 deletion arr[hg19]5p15.33p13.3 (113,577 − 31,150.935)x1 Heterozygous/ AD Cri-du-chat syndrome NA Pathogenic Subject 4 5 years/ Male Endogamous Autism spectrum disorder WES FMR1 TP-PCR (normal range of CGG repeats) SETD1A c.4175G > A, p.Arg1392His Heterozygous/ AD Neurodevelopmental disorder with speech impairment and dysmorphic facies Deleterious (SIFT), Damaging (Polyphen-2) Likely pathogenic Subject 5 1 year/ Female 2nd -degree consanguinity Delayed motor milestones, facial dysmorphisms WES CUL7 c.4651C > T p.Gln1551Ter Homozygous/ AR 3-M syndrome 1 NA Pathogenic Subject 6 Neonate (deceased)/ Male 3rd -degree consanguinity Congenital arthrogryposis, myoclonus seizures WES BRAT1 c.1313_1314del (p.Gln438ArgfsTer51) Homozygous/ AR Neonatal rigidity and multifocal seizure syndrome Damaging (MutationTaster2) Pathogenic Subject 7 2 years/ Female Endogamous Autism spectrum disorder with seizures WES SETD1B c.273 + 2T > C Heterozygous - Splice AI 0.13 (Benign) VUS Subject 8 4 years/ Male 3rd -degree consanguinity Global developmental delay WES KMT2D c.14002dup p.Thr4668AsnfsTer2 Heterozygous/ AD Kabuki syndrome NA Pathogenic Subject 9 2 years/ Female Endogamous Retinitis Pigmentosa NGS-based gene panel CRX c.585C/A p. Tyr195Ter Heterozygous/ AD Retinitis Pigmentosa NA Pathogenic Subject 10 25 years/ Female Endogamous Retinitis Pigmentosa CES CDH23 c.6514del p.Glu2173SerfsTer9 Homozygous/ AR Usher syndrome type 1D Damaging (MutationTaster2) Pathogenic Subject 11 30 years/ Male 2nd -degree consanguinity Retinitis Pigmentosa, intellectual disability NGS-based gene panel C8orf37/3 c.258delA Homozygous/ AR Bardet-Biedl syndrome-21 NA Pathogenic Subject 12 25 years/ Male Endogamous Albinism with congenital speech and hearing impairment CES MITF c.935G > G/T p.Arg318Ile Heterozygous/ AD Waardenburg syndrome type 2A Damaging (MutationTaster2) Likely pathogenic Subject 13 3 years/ Male Endogamous Squint, retino-choroidal coloboma CMA Chr. 15 arr[GRCh37] 15q13.2q13.3(31098691_32914239)x1 Heterozygous/ AD Microdeletion 15q13.2 NA Likely pathogenic Subject 14 15 years/ Male Endogamous Speech delay, behavioural issue, cafe au lait macules, Lisch nodules CES NF1 c.6855C > A p.Tyr2285Ter Heterozygous/ AD Neurofibromatosis − 1 Damaging (MutationTaster2) Pathogenic Subject 15 28 years/ Male Endogamous Night blindness, retinitis pigmentosa WES RPGR c.469 + 1G > A 5' splice site Hemizygous/ XLR Retinitis Pigmentosa-3 NA Pathogenic Subject 16 11 years/ Male Endogamous Hip displacement CES COL2A1 c.3508G > A p.Gly1170Ser Heterozygous/ AD Avascular necrosis of the femoral head Damaging (SIFT, LRT, MutationTaster2), Probably damaging (Polyphen-2) Pathogenic Subject 17 7 years/ Female 3rd -degree consanguinity Developmental delay, severe hearing loss, corpus callosum thinning NGS-based gene panel SGSH c.544C > T p.Arg182Cys Homozygous/ AR Mucopolysaccharidosis 3 Damaging (SIFT, LRT, MutationTaster2), Probably damaging (Polyphen-2) Pathogenic Subject 18 2 years/ Male Endogamous Retinal degeneration NGS-based gene panel LCAS c.1151delC p.Pro384GlnfsTer18 Homozygous/ AR Leber congenital amaurosis-5 Damaging (MutationTaster2) Pathogenic Subject 19 17 years/ Male Endogamous difficulty in night vision, retinitis pigmentosa WES EYS c.6714del p.Ile2239SerfsTer17 c.1211dup p.Asn404LysfsTer3 Compound heterozygous/ AR Retinitis Pigmentosa 25 Damaging (MutationTaster2) Pathogenic Subject 20 14 years/ Male Endogamous Ptosis, astigmatism, migraine (unspecified), muscle fatigue, b/l sensorineural hearing loss, pigmentary retinopathy, diplopia, syncope, bradycardia WES USH2A c.8167C > T p.Arg2723* Heterozygous/AR - Both disease-causing (Mutation Taster) Pathogenic c.8924T > G p.Ile2975Ser Heterozygous/AR VUS Subject 21 1 year/ Female Endogamous Afebrile seizure, parotid hemangioma, hypotonia, gas chromatography showed elevated 4-hydroxybutyric acid, glycolic acid, and 2-deoxytetronic acid. WES ALDH5A1 c.1226G > A p.Gly409Asp Compound heterozygous / AR - - Pathogenic c.274G > T p.Asp92Tyr VUS Subject 22 3 years/ Male 3rd -degree consanguinity Global developmental delay WES Mitochondrial genome sequencing (No SNV and CNV detected) SDHA c.1534C > T p.Arg512Ter Compound heterozygous / AR - - Pathogenic c.1337T > C p.Val446Ala VUS c.1346C > T p.Ala449Val VUS Subject 23 8 years/ Female non-consanguineous, non-endogamous Intellectual disability, speech and language delay, Autism spectrum disorder WES LINS1 c.1945C > T p.Gln649* Heterozygous /AR - Medium severity (REVEL) Pathogenic FBXW7 c.118G > A p.Glu40Lys Heterozygous/AD - Deleterious (SIFT) Damaging (MutationTaster) VUS Subject 24 16 years/ Female Endogamous Squint, sensitivity to light, retinitis pigmentosa CES IFT172 c.3850C > C/T p.Arg128Ter c.4775T > T/C p.Met1592Thr Compound heterozygous/ AR Retinitis Pigmentosa 71 Damaging (LRT, MutationTaster2), Likely pathogenic Subject 25 16 years/ Female Endogamous Macular dystrophy NGS-based gene panel ABCA4 c. 5371dupG p.Ala1791GlyfsTer9 Compound heterozygous / AR - Damaging (MutationTaster2) Pathogenic c.6193G > C p.Asp2065His VUS Subject 26 28 years/ Female non-consanguineous, non-endogamous Retinitis pigmentosa NGS-based gene panel PROM1 c. 1632G > T p.Gly544= Homozygous/AR Retinitis Pigmentosa − 41 NA Likely Pathogenic Subject 27 3 days (deceased)/ Female Endogamous Failure to thrive, lactic acidosis WES C1QBP c.478-7T > G Homozygous/ AR - NA VUS Subject 28 4 years/ Female Endogamous Autism spectrum disorder with cafe au lait macules WES UBE3A c.1255C > G p.Pro419Ala Heterozygous/ AD NA VUS Subject 29 7 years/ Female Endogamous Intellectual disability with Autism spectrum condition WES VWF c.2447G > A p.Arg816Gln Heterozygous/AD Von-Willebrand disease NA Likely pathogenic NA CMA Chr.12 arr[GRCh37] 12p13.33 (173786_316360)x1 12p13.33 Microdeletion Pathogenic Subject 30 5 months/ Female 3rd -degree consanguinity Hypotonia, floppy infant, developmental delay MLPA ( SMN1 & SMN2 gene) SMN1 SMN2 Exon7 copy no.3 Exon 8 copy no.3 Exon 7 copy no.1 Exon 8 copy no.1 Heterozygous/AR - NA VUS WES TNNT1 c.649T > A p.Cys217Ser Homozygous/AR - Benign (PolyPhen2, MutationTaster2) VUS Subject 31 8 years/ Male Endogamous Intellectual disability, moderate, thin corpus callosum, cerebral white matter hypoplasia, apneic episodes, seizures, facial dysmorphism WES MS-MLPA (Prader-Willi and Angelman syndrome, negative) FMRI gene TP-PCR (negative) KNL1 c.3493G > A p.Glu1165Lys Homozygous/AR - Tolerated(SIFT), Benign (Polyphen2) VUS SYNJ1 c.2125C > T p.Arg709* Heterozygous/AR - Tolerated SIFT VUS CFTR c.2756A > G p.Tyr919Cys Heterozygous/AR - Damaging (Polyphen2, MutationTaster2) VUS Subject 32 5 years/ Male Endogamous Autism spectrum disorder WES FMRI gene TP-PCR (negative) No variant detected - Subject 33 11 years/ Male Endogamous B/l Sensorineural hearing loss WES TRRAP c.5146G > A p.Gly1716Arg Heterozygous/ AD - Damaging (SIFT, MutationTaster2) VUS Subject 34 2 years/ Female Endogamous Global developmental delay, autism spectrum disorder, cafe au lait macules, WES SCAF4 c.3246G > C; p.Glu1082Asp Heterozygous/AD - Damaging -SIFT, MutationTaster2 VUS CNTNAP2 c.2956G > A; p.Gly986Ser Heterozygous /AD - Damaging- SIFT, MutationTaster2 VUS PNPT1 c.716A > C; p.Gln239Pro Heterozygous /AD - Tolerated SIFT, Damaging MutationTaster2 VUS Subject 35 2 years/ Female Endogamous Motor developmental delay, mild dysmorphisms, Kidney small with increased echogenicity, WES SMC1A c.1847C > T p.Ala616Val Heterozygous / XLD - Damaging (SIFT, LRT, MutationTaster2, Polyphen-2) VUS Subject 36 1 year/ Female 3rd -degree consanguinity Global developmental delay WES CMA No variant detected - - VUS Subject 37 10 years/ Male Endogamous Retinoblastoma CES CMA MLPA ( RB1 gene) No variants reported - - Subject 38 2 years/ Female Endogamous Global developmental delay CMA Increased ROH in chromosomes 5q and 16q - - - WES ARID2 c.1075delG, p.Val359Leufs*5 Heterozygous/ AD Coffin-Siris syndrome NA Likely Pathogenic Legend: CES- Clinical Exome Sequencing, WES- Whole Exome Sequencing, CMA- Chromosomal Microarray, MS-MLPA- Methylation-specific Multiplex Ligation dependant Probe Amplification, MLPA- Multiplex Ligation dependant Probe Amplification, TP-PCR- Triplet Primed Polymerase Chain Reaction, AD- Autosomal Dominant, AR- Autosomal Recessive, XLD- X-Linked Dominant, XLR- X-linked Recessive, NGS- Next-Generation Sequencing, SNV- Single Nucleotide Variant, CNV- Copy Number Variant, NA- Not Available, ROH- Regions Of Homozygosity, VUS- Variant of Uncertain Significance Results A total of 38 subjects of Asian Indian ethnicity with paediatric-onset referrals who underwent genetic counseling and testing were reviewed (Table 1). The clinical symptoms and genomic results of all 38 subjects are provided in Table 2 . Thirteen subjects had ophthalmic conditions such as RP, macular dystrophy, retinoblastoma, and albinism with deaf mutism. Eighteen subjects had clinical manifestations of NDDs, and their symptoms comprised speech delays, reduced response to name calls, lack of eye contact, receptive language delays, expressive language delays, delayed motor milestones, restricted and repetitive behaviors, social communication deficits, and hyperactivity. Based on the developmental pediatrician’s assessment, clinical diagnoses comprised either ASD, ADHD, ID, or GDDs. Seven had other pediatric indications (orthopedic conditions, hearing impairment, and inborn error of metabolism) that did not fall under ophthalmic or NDD indications. Amongst the ophthalmic subjects, 84.6% (11/13) carried pathogenic/likely pathogenic (P/LP) variants in candidate genes that could explain the clinical phenotype and mode of inheritance. In subjects 9, 10, 11, 12, 13, 14, 15, 18, 19, 24, and 26 (Table 2 ), a syndromic diagnosis such as Usher syndrome, Bardet-Biedl syndrome, Waardenburg syndrome type 2A, microdeletion 15q13.2, neurofibromatosis type 1, and Leber congenital amaurosis was confirmed. In 7.7% (1/13) of ophthalmic subjects, genetic results had a P/LP variant and VUS combination in the same gene involved in AR disease, and 7.7% (1/13) had no molecular genetic variants identified. In the NDD group, 44.4% (8/18) had P/LP variants in candidate genes that could explain the clinical phenotype and mode of inheritance. Subjects 1, 3, 4, 5, 8, 17, 29, and 38 had genetic diagnoses of Cantu syndrome, Cri-du-chat syndrome, neurodevelopmental disorder with speech and dysmorphic facies, 3-M syndrome, Kabuki syndrome, mucopolysaccharidosis type 3, 12p13.33 microdeletion syndrome, and Coffin-Siris syndrome. 11.1% (2/18) had combinations of P/LP variants and VUS in the same gene involved in AR disease, and in 44.4% (8/18), only VUS or no molecular genetic variants were identified. In subjects with other pediatric conditions, 42.8% (3/7) had a genetic diagnosis established with P/LP variants in genes explaining the clinical phenotype. Subjects 2, 6, and 16 were diagnosed with cystic fibrosis, neonatal rigidity, and multifocal seizure syndrome and avascular necrosis, respectively. In 28.5% (2/7), there were combinations of P/LP variants and VUS in the same gene involved in AR disease, and in 28.5% (2/7), there was no genetic diagnosis confirmed. Secondary and clinically actionable incidental findings As per recommendations for reporting secondary and clinically actionable incidental findings (Miller et al., 2021), variants were reported in 2 subjects. Subject 20 had a homozygous pathogenic variant associated with partial biotinidase deficiency in the BTD gene (c.1336G > C, p.Asp446His). Interestingly, the primary diagnosis was yet ambiguous (parents were counseled regarding further testing for segregation of the USH2A variants by Sanger sequencing and testing for mitochondrial deletions in the proband) alongside medications to address his biotinidase deficiency prescribed by our clinician (MJ). Subject 29 (primary diagnosis of 12p13.3 microdeletion syndrome) was identified with a heterozygous likely pathogenic variant in the VWF (von Willebrand factor) gene (exon19: c.2447G > A, p.Arg816Gln) associated with autosomal dominant (AD) von Willebrand disease. She was further referred for a hematological follow-up to direct appropriate prophylaxis and management. Both findings were explained during post-test genetic counseling and confirmed by the clinicians in our group (MJ and SS). We provide below the clinical presentations and genetic output of six representative subjects (indicated by arrows), two from each category, with their pedigrees depicted in Fig. 1 . Post-test genetic counseling for each group is addressed. Pedigree symbols are as per the standardized nomenclature (Bennett et al., 2008). Ophthalmic group Subject 25 A 16-year-old female, born of a non-consanguineous marriage with no family history, was clinically diagnosed with macular dystrophy. She reported blurred vision, distant and near, since age 12. Her BCVA was 6/7.5 in both eyes, which declined to 6/18P in the right eye and 6/12P in the left eye with N8 in both eyes over 4 years. Fundus examination revealed normal vessels and discs but a bull's-eye lesion in the macula. Fundus autofluorescence indicated hypoautofluorescence, suggesting retinal pigment epithelium atrophy. OCT revealed the absence of inner and outer retinal layers and a loss of inner and outer segment junction layers. Multifocal ERG recorded reduced central foveal spike and parafoveal responses, suggestive of reduced macular cone photoreceptor function. Her parents opted for an NGS-based retinal degeneration gene panel test that revealed heterozygous variants in the ABCA4 gene (pathogenic variant in exon 38: c.5371dupG, p.Ala1791GlyfsTer9 and a VUS in exon 45: c.6193G > C, p.Asp2065His). We counseled the family on parental testing for the phasing of the variants and clinical surveillance for disease progression (Tanna et al., 2017). We informed them that the VUS may likely be reclassified as causative based on additional supportive evidence (Miranda Durkie, 2024) that could substantiate the presence of the pathogenic variants in trans with VUS, as demonstrated previously (Gupta et al., 2023). Subject 37 A 9-year-old male child born to non-consanguineous parents with no family history was evaluated for leukocoria at 6 months and diagnosed with bilateral retinoblastoma. Two small-sized tumors were detected in the superonasal and the inferonasal quadrant of the right eye (group A retinoblastoma) (Ancona-Lezama et al., 2020), while a subretinal yellowish-white mass filling the vitreous cavity with retinal detachment (group E retinoblastoma) was observed. A B-scan of the left eye showed high echogenic areas of focal calcification, and brain and orbit computed tomography was suggestive of optic nerve infiltration in the left eye. He underwent left eye enucleation with a primary implant, and the right eye was treated with laser radiation. Histopathology confirmed features of well-differentiated retinoblastoma infiltrating the lamina cribrosa with tumor-free margins of the optic nerve and choroid. He received 4 cycles of adjuvant chemotherapy. The parents were planning another pregnancy and opted for an NGS-based CES. There was no identifiable genetic variant through blood sampling, and the tumor tissue was unavailable for genetic testing; the coverage of the exons of the RB1 gene was 100%. The parents pursued additional genetic testing, such as RB1 gene exon deletion/duplication via MLPA and CMA, to check for copy number variants that returned negative results. As the parents had expectations from the genetic test to help them plan their next pregnancy, we explained that a yet unidentified de novo mutation is likely responsible for the disease manifestation. The recurrence risk is much lower than in autosomal dominant retinoblastoma, but could be as much as 5% due to germline mosaicism. As no causative variant was found, this cannot be tested prenatally. The parents were counseled on options for early ophthalmic screening for future offspring to prevent low vision, blindness, and other morbid outcomes based on current guidelines (Schaiquevich et al., 2022, Skalet et al., 2018). Neurodevelopmental disorders (NDDs) group Subject 23 An 8-year-old female child born to non-consanguineous parents and with no family history was diagnosed with ASD. The psychological evaluation indicated a developmental and social age equivalent to a 3-year and 8-month level. The parents were planning their next pregnancy and opted for WES for their child. Results revealed a heterozygous likely pathogenic nonsense variant in the LINS1 gene (exon 7: c.1945C > T, p.Gln649*) associated with AR intellectual developmental disorder, but no second causative variant was found. This could imply the possibility of a second mutation yet unidentified or an incidental carrier status for an autosomal recessive disorder and warrants additional screening, such as for copy number variants. A heterozygous missense VUS in the FBXW7 gene (exon 4: c.118G > A, p.Glu40Lys) was additionally detected. The gene is associated with AD developmental delay with hypotonia and language impairment. The heterozygous VUS in the FBXW7 gene could be de novo , and parental testing is needed to confirm the origin (Miranda Durkie, 2024). The parents were counseled regarding these options; however, they did not proceed with testing owing to the high costs incurred and conveyed that they would reconsider this over time. Subject 36 A 1-year-4-month-old female child born to 3rd-degree consanguineous parents was diagnosed with GDD. Prenatal second-trimester scans showed a fetus with an unossified nasal bone, splaying of the neural arch of the last sacral vertebra, prenasal edema, persistent left superior vena cava, and small fetal size for gestational age. She was delivered via an emergency cesarean section due to fetal distress and meconium-stained liquor. The birth cry was delayed, requiring resuscitation. Facial dysmorphism included low-set ears, hypertelorism, synorphys, high-arched palate, long philtrum, microcephaly, low hairline, retrognathia, and hemangioma on the spine. She had acyanotic congenital heart disease with pseudostrabismus. The magnetic resonance imaging (MRI) brain suggested periventricular leukomalacia as a hypoxic-ischemic sequelae. The parents sought an accurate diagnosis for improved management beyond current physiotherapy and speech-swallow therapy. Genetic testing that comprised CMA, WES, and karyotyping was negative for any variants. Addressing such possibilities during pre-test genetic counseling was instrumental for the parents to cope with the negative results of expensive tests. Currently, she is on clinical surveillance and advised a periodic reanalysis of results. Other Paediatric Conditions Group Subject 21 A 4-month-old female child, born to non-consanguineous, endogamous parents, had no prior family history and presented with infantile parotid hemangioma and unprovoked seizures from 1 month of age. She had hypotonia, complete head lag in the pull-to-sit position, and plagiocephaly with a flattened right occipital bone. Hammersmith's infant neurological examination score was 40/78, with a minimum score of 67 considered normal between ages 3–6 months (Romeo et al., 2022). Auditory and ophthalmic examinations, MRI, and 3D computed tomography of the brain were normal. Metabolic screening via gas chromatography showed increased levels of 4-hydroxybutyric acid-2 (3.46 MoM/NMT 1.87) and 2-deoxytetronic acid-3 (1.59 MoM/NMT 0.91), both of which were confirmed on repeat testing. Concerned about the diagnosis and recurrence in future pregnancies, the parents opted for trio-based WES. The child had heterozygous variants in the ALDH5A1 gene (a pathogenic exon 8: c.1226G > A, p.Gly409Asp variant and a VUS in exon 1: c.274G > T, p.Asp92Tyr). Parental exome sequencing established the compound heterozygosity in the child. The ALDH5A1 gene is implicated in autosomal recessive succinic semialdehyde dehydrogenase deficiency (OMIM#271980), also called 4-hydroxybutyric aciduria, which is an ultra-rare monogenic disorder of the gamma-aminobutyric acid (GABA) metabolism that usually exhibits clinical heterogeneity. Affected persons receive symptomatic management and therapy for neurobehavioral symptoms (Didiasova et al., 2020). This subject had elevated levels of 4-hydroxybutyric acid-2. This endorsed a biochemical diagnosis, and the presence of compound heterozygous variants (pathogenic and VUS) in the ALDH5A1 gene substantiated an etiologic linkage, as co-segregation too was established in this case. This was explained to the parents, and we discussed options to re-analyze the VUS and how these linked single-nucleotide variants could impact future reproductive choices (prenatal and pre-implantation genetic testing). Subject 16 An 11-year-old male child, born of a non-consanguineous marriage, presented with symptoms of gait abnormality. The X-ray of the pelvis was suggestive of bilateral avascular necrosis, and the MRI of the pelvis showed features of bilateral Perthes disease. Family pedigree revealed multiple members similarly affected on the proband’s paternal side (father, grandfather, uncle, cousins, and great-grandmother), with three of them having undergone hip-replacement surgeries. The parents chose to proceed with CES for the subject, which revealed the presence of a heterozygous pathogenic variant in the COL2A1 gene (exon 50: c.3508G > A, p.Gly1170Ser), confirming a diagnosis of autosomal dominant avascular necrosis of the femoral head (OMIM#608805). The clinical presentation, family pedigree, and molecular genetic findings in this subject were in synchrony, which helped to counsel the family towards considering molecular confirmation of other similarly affected members and advise those willing on risk estimation. Discussion Genetic diagnosis and counseling between the groups In our study, we retrospectively analyzed the clinical presentations of 38 subjects with genetic test findings in the context of genetic counseling. It was seen that 84.6% of subjects belonging to ophthalmic, 44.4% to NDDs, and 42.8% to other pediatric conditions had a confirmed molecular genetic diagnosis established with P/LP variants, matching the clinical symptoms. Ophthalmic conditions have a higher success rate in clinical and genetic diagnoses as they are predominantly monogenic. In our study, 44.4% of NDD subjects remained with uncertain/uninformative results against 7.7% and 28.5% in the ophthalmic and other-pediatric conditions groups, respectively. A meta-analysis published recently (Britten-Jones et al., 2023) showed that NGS aided in an accurate diagnosis in 61.3% of persons with inherited retinal diseases. The diagnostic output of genetic tests for NDDs is variable; CMA (9–13%), exome sequencing with re-analysis (26–30%), whole genome sequencing (WGS) (40–45%) (Lee and Nelson, 2020), and up to 2.5% for fragile-X syndrome testing of males with ID (Carter et al., 2023b). The diagnostic yield is 21–80% for all pediatric conditions pooled (Lee, 2023), wherein subspecialties of ophthalmology and inborn errors of metabolism were amongst the highest. Ambiguity in genetic results is common in the post-genomic era (Newson et al., 2016), with clinical and genetic heterogeneity present in different pediatric sub-specialties. Advancements in genetic diagnostic techniques have transformed the speed and accuracy of diagnosis in many individuals and families who never knew the cause of their condition for years (Stark et al., 2016a). This was evident as seen in subject 16, whose molecular diagnosis was missed across three generations. In this family, molecular confirmation with post-genomic techniques was achieved within days, as opposed to waiting for decades. Avascular necrosis of the femoral head is caused by the disruption of blood supply to the proximal femur, resulting in osteocyte death. It can result from traumatic (fracture, hip dislocation) or non-traumatic causes (corticosteroid use, alcoholism, sickle cell disease, bone marrow transplant, etc.), with Legg-Calve-Perthes disease being the most common cause when it occurs in children. It shares the same histopathological feature of osteonecrosis but is restricted to the hip joints and can be caused by highly penetrant variants in the COL2A1 gene. With a variable age of onset, prior knowledge of a person’s risk aids in better management and prognosis, and this was communicated to the family, too (Asadollahi et al., 2021, Chen et al., 2004). Genetic counseling in uncertain and uninformative results Genetic counselors' role in delivering information regarding outcomes of genetic tests to families in an understandable manner is critical in this post-genomic era, as it facilitates an informed decision to pursue genetic testing based on the clinical condition a child presents with. Uncertain and uninformative results from genetic testing carry with them the prior responsibility of preparing families for such a possibility during pre-test genetic counseling to effectively communicate and help parents cope with such results (Thomassen Hammerstad et al., 2020, Bartley et al., 2020). The possibility of such results varies and could depend on whether the condition is predominantly monogenic or multifactorial in etiology. Variants are classified based on current knowledge of their disease associations, and in laboratory practice, VUSs are reported as part of genetic results when there is an opportunity to explore their role in disease manifestation, as delineated by the Association for Clinical Genomic Science (Miranda Durkie, 2024). Gathering additional evidence could allow reclassification. This could be parental genetic testing to determine if a variant is de novo , to confirm cis or trans phasing of heterozygote variants for a suspected recessive condition, testing affected relatives to derive co-segregation, clinical investigations for phenotypic specificity, or performing functional studies (Miranda Durkie, 2024). VUSs must be treated with caution in the diagnostic journey of pediatric conditions, as the patient's families often bear the burden of such an ambiguous result (Li et al., 2019). In genetic counseling, they are interpreted based on whether they are reported in isolation or in conjunction with other P/LP variants (Miranda Durkie, 2024), phenotype matches, etc., as discussed below. Subject 25 had a clinical diagnosis of macular dystrophy, with a combination of a pathogenic variant with a VUS in the ABCA4 gene. The ABCA4 gene, apart from other retinal dystrophies, is also implicated in autosomal recessive Stargardt disease and presents in childhood with variable disease manifestations. In instances of VUSs in combination with a P/LP variant for a gene associated with autosomal recessive inheritance, parental segregation can be useful to gather evidence for reclassification, as was conveyed to the family. Similar results were seen in subject 21, with a suspected inborn error of metabolism and a combination of a pathogenic variant and VUS in the ALDH5A1 gene. In this family, the parents chose trio WES, and the variants were found to be in trans , with the metabolic investigations clinically supportive of a causative diagnosis. Subject 37 had bilateral retinoblastoma with no genetic variant identified after three different genetic tests were performed. Retinoblastomas are one of the most highly curable pediatric neoplasms, with a disease-free survival exceeding 90% (Schaiquevich et al., 2022, Kaliki et al., 2023). While the genetic test results were uninformative, the clinical diagnosis was unambiguous. In this family with no prior history, risk estimation for future pregnancies followed current guidelines (Skalet et al., 2018). Subject 36, clinically diagnosed with GDD, was similarly left with no conclusive results after having performed three genetic tests. As per current estimates, approximately 50% of patients with NDDs remain undiagnosed for causative genomic variants. Here, too, the parents went as far as they could, out of their will to identify the root cause of their child’s condition. An uninformative result impacts achieving a diagnosis and downstream management opportunities. Periodic reanalysis may provide answers when improved bioinformatics and the discovery of new genes are available over time (Stark et al., 2019). Genetic counseling (pre- and post-test) hence becomes crucial in families with uninformative results, preparing them for the journey ahead (Fonda Allen et al., 2016, Cormack et al., 2024). Genetic counselors facilitate decision-making and do not make decisions themselves when it comes to genetic testing. Families have multiple considerations, such as how the diagnosis can change management, how much the test costs, possible results of the tests, etc., when they make their choice to test (or not) (Stein et al., 2018). Subject 23 was diagnosed with ASD and had a heterozygous pathogenic variant in the LINS1 gene with no additional variant detected. The option of tests that could detect copy number changes was discussed, but the parents chose to defer their decision to pursue additional testing, with cost consideration being a primary reason. The cost to sequence the entire human genome has drastically reduced from US $ 300 million when the initial draft was published to the current value of less than US $ 1000 (Hayden, 2014). In our outsourced laboratories, WES costs around US $ 238.15 (INR 20,000; 1 USD on September 2024 = INR 83.98). Even so, genetic testing is not yet popular with families, as the cost in low- and middle-income countries is still high (Zhong et al., 2021, Nahar et al., 2013). Families of children with NDDs often face severe caregiver fatigue and financial burden owing to the high cost of rehabilitation therapies (Maridal et al., 2021). Also, the utility of genetic testing is perceived differently (2015), and in Asian countries such as India, the authority to make decisions, for healthcare included, can rest upon the opinions of individuals up to the immediate or extended family (Weil, 2001) (Young et al., 2021). Genetic counseling for secondary and clinically actionable incidental findings Families must be educated during pre-test genetic counseling on possible reporting of secondary and incidental findings resulting from exome sequencing. As per the policy statement of the ACMG, laboratories can disclose variants in genes that are clinically actionable and secondary findings apart from the primary indication of the test (Miller et al., 2021). Subjects 20 and 29 had secondary and clinically actionable incidental findings reported as part of NGS results, and they were previously aware of such a possibility, which made disclosure and discussion toward clinical management peaceful. In our study, genetic testing was opted for by parents on an awareness and socioeconomic basis and was not uniform for all the subjects, a limitation we acknowledge. Trio WES, which can improve the diagnostic rate in NDDs (Gao et al., 2019) was also not performed in all subjects due to socioeconomic or personal reasons. In instances of subjects with either only VUSs or no results, some families chose to proceed with additional testing (for example, parental segregation, exome sequencing, or copy number variant analysis), while some did not. We believe this is a kaleidoscopic view of the incorporation of genetic testing from a socio-economic and cultural perspective. In this era of high-throughput diagnostic technology, a confirmed diagnosis has been possible for many affected individuals with impactful consequences for their families (Ramos, 2020). The role of genetic counselors in the pediatric setting is more pertinent now than ever, as it helps clinicians and parents navigate the uncertainties of genomic results and aids informed decision-making. Conclusions The post-genomic era has augmented healthcare delivery at an unprecedented pace with accelerated diagnosis of rare pediatric conditions. On the other hand, a consequence of such high-throughput technology is uncertain and uninformative results, be it in ophthalmic, NDDs, or other pediatric conditions, and variably so. We reiterate that pre- and post-test genetic counseling is crucial to facilitate this understanding to affected individuals and their families and guide them towards informed choices. There are barriers, too, to the adoption of genomic services globally (Zhong et al., 2021), and we believe we are amidst concerted efforts by ophthalmologists, pediatricians, laboratory analysts, allied therapists, nursing practitioners, and genetic counselors to overcome this challenge. Molecular genetic diagnosis through NGS screening has transformed and improved the genetic counseling process, unlike in the pre-genomic era, and continues to expand its footprint in healthcare delivery. Declarations Conflict of Interest : Brinda Ramanathan, Sunita Mohan, Deepika Karthik Kumar, Sugirdhana Parthiban Ramsait, Meenakshi Jayndhyala, Subramanian Sethuraman, Hubert Smeets, and Govindasamy Kumaramanickavel declare that they have no conflict of interest. Funding: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript Ethics approval : Ethics approval was obtained from M.N. Eye Hospital Private Limited (Reg. No.: ECR/249/Indt/TN/2015/RR-18). 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R., YAP, P., WALSH, M., YEUNG, A., PETERS, H., MORDAUNT, D., COWIE, S., AMOR, D. J., SAVARIRAYAN, R., MCGILLIVRAY, G., DOWNIE, L., EKERT, P. G., THEDA, C., JAMES, P. A., YAPLITO-LEE, J., RYAN, M. M., LEVENTER, R. J., CREED, E., MACCIOCCA, I., BELL, K. M., OSHLACK, A., SADEDIN, S., GEORGESON, P., ANDERSON, C., THORNE, N., GAFF, C. & WHITE, S. M. 2016a. A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders. Genetics in Medicine, 18 , 1090-1096. STARK, Z., TAN, T. Y., CHONG, B., BRETT, G. R., YAP, P., WALSH, M., YEUNG, A., PETERS, H., MORDAUNT, D., COWIE, S., AMOR, D. J., SAVARIRAYAN, R., MCGILLIVRAY, G., DOWNIE, L., EKERT, P. G., THEDA, C., JAMES, P. A., YAPLITO-LEE, J., RYAN, M. M., LEVENTER, R. J., CREED, E., MACCIOCCA, I., BELL, K. M., OSHLACK, A., SADEDIN, S., GEORGESON, P., ANDERSON, C., THORNE, N., MELBOURNE GENOMICS HEALTH, A., GAFF, C. & WHITE, S. M. 2016b. A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders. Genet Med, 18 , 1090-1096. STEIN, Q., LOMAN, R. & ZUCK, T. 2018. Genetic Counseling in Pediatrics. Pediatrics In Review, 39 , 323-331. STEWART, K. 2018. The Certainty of Uncertainty in Genomic Medicine: Managing the Challenge. Journal of Healthcare Communications, 03. TANNA, P., STRAUSS, R. W., FUJINAMI, K. & MICHAELIDES, M. 2017. Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options. British Journal of Ophthalmology, 101 , 25-30. TEKOLA-AYELE, F. & ROTIMI, C. N. 2015. Translational Genomics in Low- and Middle-Income Countries: Opportunities and Challenges. Public Health Genomics, 18 , 242-7. THE LANCET GLOBAL, H. 2024. The landscape for rare diseases in 2024. The Lancet Global Health, 12 , e341. THOMASSEN HAMMERSTAD, G., SARANGI, S. & BJØRNEVOLL, I. 2020. Diagnostic uncertainties, ethical tensions, and accounts of role responsibilities in genetic counseling communication. J Genet Couns, 29 , 1159-1172. VERMA, I. C., PALIWAL, P. & SINGH, K. 2018. Genetic Testing in Pediatric Ophthalmology. The Indian Journal of Pediatrics, 85 , 228-236. WEIL, J. 2001. Multicultural education and genetic counseling. Clinical Genetics, 59 , 143-149. YOUNG, J. L., MAK, J., STANLEY, T., BASS, M., CHO, M. K. & TABOR, H. K. 2021. Genetic counseling and testing for Asian Americans: a systematic review. Genet Med, 23 , 1424-1437. ZABLOTSKY, B., BLACK, L. I., MAENNER, M. J., SCHIEVE, L. A., DANIELSON, M. L., BITSKO, R. H., BLUMBERG, S. J., KOGAN, M. D. & BOYLE, C. A. 2019. Prevalence and Trends of Developmental Disabilities among Children in the United States: 2009-2017. Pediatrics, 144. ZHONG, A., DARREN, B., LOISEAU, B., HE, L. Q. B., CHANG, T., HILL, J. & DIMARAS, H. 2021. Ethical, social, and cultural issues related to clinical genetic testing and counseling in low- and middle-income countries: a systematic review. Genet Med, 23 , 2270-2280. ZSCHOCKE, J., BYERS, P. H. & WILKIE, A. O. M. 2023. Mendelian inheritance revisited: dominance and recessiveness in medical genetics. Nature Reviews Genetics, 24 , 442-463. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. 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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-7063331","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":483062552,"identity":"56675eb3-8930-40b8-b98e-a2ae10bb4107","order_by":0,"name":"Brinda Ramanathan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIiWNgGAWjYBACAwbGBgYeMBNM2gAxY+MB4rSwgck0kJYGAlpg5kO0HAaL4tViLn247cGbGobE/vm9hz/83HHebm37YaAtNTbRuLRY9iW2G845xpA44xhfmmTvmdvJ284kArUcS8ttwOWwM4xt0jxsDMYMx3jMGHjbbiebHQBqYWw4TEDLPwZj+WM8xh//tp1LNjv/kAgtvG0McgbHeAyAjAN2ZjcI2GLZw9gmObdPQs7wWI6ZtGxbcoLZDaAtCXj8Ys7D/kzizTcbHrnDZ4w/vm2zszc7n/7wwYcaG5xaoEACzkoEq0zArxwV2JOieBSMglEwCkYGAACz6V5LfdO3rQAAAABJRU5ErkJggg==","orcid":"","institution":"Maastricht University","correspondingAuthor":true,"prefix":"","firstName":"Brinda","middleName":"","lastName":"Ramanathan","suffix":""},{"id":483062553,"identity":"6eb3c06b-65c6-44dc-8eec-fc4dab47e128","order_by":1,"name":"Sunita Mohan","email":"","orcid":"","institution":"GenVams Trust","correspondingAuthor":false,"prefix":"","firstName":"Sunita","middleName":"","lastName":"Mohan","suffix":""},{"id":483062554,"identity":"b28ba4e3-940a-428c-be2f-173b39c6f306","order_by":2,"name":"Deepika Karthik Kumar","email":"","orcid":"","institution":"Maastricht University","correspondingAuthor":false,"prefix":"","firstName":"Deepika","middleName":"Karthik","lastName":"Kumar","suffix":""},{"id":483062555,"identity":"6f9721a2-d437-493b-9f8f-da3ecfa99ebe","order_by":3,"name":"Sugirdhana Parthiban Ramsait","email":"","orcid":"","institution":"GenVams Trust","correspondingAuthor":false,"prefix":"","firstName":"Sugirdhana","middleName":"Parthiban","lastName":"Ramsait","suffix":""},{"id":483062556,"identity":"38422770-b0e9-48a7-aa29-36e687a2722f","order_by":4,"name":"Meenakshi Jayndhyala","email":"","orcid":"","institution":"Nishta Integrated Neurodevelopment Centre","correspondingAuthor":false,"prefix":"","firstName":"Meenakshi","middleName":"","lastName":"Jayndhyala","suffix":""},{"id":483062562,"identity":"71ec1589-87e9-4e68-97fa-89cd10c14775","order_by":5,"name":"Subramanian Sethuraman","email":"","orcid":"","institution":"Nishta Integrated Neurodevelopment Centre","correspondingAuthor":false,"prefix":"","firstName":"Subramanian","middleName":"","lastName":"Sethuraman","suffix":""},{"id":483062563,"identity":"a20a9388-efcf-4199-8e81-9978c4e12811","order_by":6,"name":"Hubert Smeets","email":"","orcid":"","institution":"Maastricht University","correspondingAuthor":false,"prefix":"","firstName":"Hubert","middleName":"","lastName":"Smeets","suffix":""},{"id":483062564,"identity":"562efc49-c610-4291-8ae0-a43bfa327c33","order_by":7,"name":"Govindasamy Kumaramanickavel","email":"","orcid":"","institution":"GenVams Trust","correspondingAuthor":false,"prefix":"","firstName":"Govindasamy","middleName":"","lastName":"Kumaramanickavel","suffix":""}],"badges":[],"createdAt":"2025-07-07 08:53:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7063331/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7063331/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":86656347,"identity":"342996c7-8c90-42d8-bd7c-b09dd397307d","added_by":"auto","created_at":"2025-07-14 10:19:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":156805,"visible":true,"origin":"","legend":"\u003cp\u003ePedigree charts of subjects 25, 37, 23, 36, 21, and 16\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7063331/v1/a9fd0b977dac646e19d5265e.png"},{"id":98441410,"identity":"b2880fee-a4dc-483f-be1c-47864b345337","added_by":"auto","created_at":"2025-12-17 17:05:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1341254,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7063331/v1/2a1770cb-668c-49a7-8da6-434c1a894296.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Post-Genomic Era: Critical Role of Genetic Counseling in a Pediatric Clinic","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMany pediatric-onset diseases and congenital anomalies have a genetic etiology (Lee, 2023, McCandless et al., 2004). Advances in genetic testing, such as next-generation sequencing (NGS), have improved healthcare by facilitating accurate diagnosis and genetic counseling of rare pediatric disorders (Nguengang Wakap et al., 2020). Close to 70% of rare genetic disorders occur in childhood, with an average of 4.8 years taken for a definite diagnosis (The Lancet Global, 2024). Genetic diagnoses have various implications. It is a means of closure to diagnostic odysseys (Michaels-Igbokwe et al., 2021) and helps families understand their child’s medical and genetic issues. For healthcare providers, a definite diagnosis aids in the prognosis, direct management, and rehabilitation referrals in setting realistic expectations for the future, including preparing for to-emerge comorbidities (Lalonde et al., 2020, Robin, 2006, Hong et al., 2019). Identifying the genetic cause of pediatric-onset conditions can improve clinical outcomes (Stark et al., 2016b), reduce diagnostic costs (Dragojlovic et al., 2018), and help parents make informed reproductive choices (Elliott, 2020). In the past, diagnostic processes addressed common chromosomal aberrations and monogenic disorders with accompanying laboratory tests that interrogated genes preselected on clinical symptoms or, for example, on biochemical investigations (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). However, this approach has evolved in the post-genomic era to a gene-first strategy, where targeted gene panels, whole exome or whole genome sequencing, or chromosomal microarray is performed as the first step in the diagnostic process.\u003c/p\u003e\u003cp\u003eGenetic counseling, by definition of the National Society of Genetic Counselor’s Task Force report, is the process of helping people to understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease and enable them to make informed decisions (Resta et al., 2006). A genetic counselor’s role transcends the stages of establishing a diagnosis and continues to support families via multidisciplinary teams involving the clinician, laboratory analysts, and other rehabilitation therapists as necessary. Additionally, in this post-genomic era, where genomic tests are performed for monogenic and multifactorial disorders (Couser et al., 2021, Morad et al., 2007, Aldharman et al., 2023, McGlynn and Langfelder-Schwind, 2020), genetic counselors have to educate patient families about the possible outcomes of genomic tests (confirmed or negative for genomic variants, variants of uncertain significance [VUS], secondary or incidental findings) during pre-test genetic counseling (Federici and Soddu, 2020), as this may impact the establishment of an accurate diagnosis, subsequent management, and reproductive options for the patients and parents (Elliott, 2020). Pediatric-onset conditions show wide clinical and genetic heterogeneity. They can be monogenic, like in retinitis pigmentosa (RP) and cystic fibrosis, or, as in pediatric neurodevelopmental disorders (NDDs), be monogenic or complex with multiple genes and environmental factors interfacing (Zschocke et al., 2023, Verma et al., 2018, Carter et al., 2023a, 2024).\u003c/p\u003e\u003cp\u003eThere are 300 + genes responsible for monogenic inherited retinal degenerative disorders (Holanda et al., 2024) with an estimated prevalence of 1 in 2000 persons, and it affects close to two million people worldwide (Lam et al., 2021). Precise diagnosis is challenging due to the extensive clinical heterogeneity, but advances in DNA sequencing technology have made it easier to find the genetic cause, as they are generally monogenic. The gene-first approach pays off. For instance, retinitis pigmentosa (RP) may overlap with clinical symptoms of Leber congenital amaurosis or cone-rod dystrophy(Chung and Traboulsi, 2009, Moore, 1992) or be associated with non-syndromic and syndromic forms (ciliopathies, mitochondrial disorders, etc. (Fuster-García et al., 2021)), and this difference in diagnosis can be cleared with molecular genetic testing.\u003c/p\u003e\u003cp\u003eNDDs such as autism spectrum disorder (ASD), global developmental delay (GDD), attention deficit hyperactivity disorder (ADHD), and intellectual disability (ID), diagnosed as per the \u003cem\u003eDiagnostic and Statistical Manual of Mental Disorders, 5th edition\u003c/em\u003e (DSM-5) (Hamanaka et al., 2022, Hu et al., 2014, Association, 2013) affect more than 3% of children worldwide (Parenti et al., 2020) with 1 in 36 children diagnosed with autism alone (Zablotsky et al., 2019, Prevention, 2023). In addition, they exhibit wide phenotypic and genetic heterogeneity (Choi et al., 2021, Bosch et al., 2023, Arnett and Flaherty, 2022, Márquez-Caraveo et al., 2021). Genetic testing for NDDs is tiered and directed by established guidelines owing to their complex etiology (Miller et al., 2010, Srivastava et al., 2019). Close to 40% of NDDs have documented monogenic causes, detected through exome sequencing (2017), and 9–13% have copy number variants (Lee and Nelson, 2020). This leaves a majority genetically uncharacterised and attributable to multifactorial and oligogenic causes or Mendelian genes that are yet to be identified. Other pediatric-onset genetic disorders in disciplines such as neurology, orthopedics, endocrinology, and pulmonology involving conditions such as inborn errors of metabolism, sensorineural hearing loss, mitochondrial disorders, avascular necrosis, etc., also have genomic variations ranging from copy number variations to monogenic sequence changes (Lalonde et al., 2020, Stein et al., 2018).\u003c/p\u003e\u003cp\u003eVariants identified through genomic testing are classified according to ACMG/AMP guidelines as pathogenic, likely pathogenic, VUS, likely benign, or benign (Richards et al., 2015). NGS, globally, has no doubt improved diagnostic accuracy and enabled personalized treatment and prevention. However, genomic investigations returning with VUSs or uninformative results are a possibility, whether the condition is monogenic or multifactorial, and add a layer of complexity to genetic counseling in pediatrics (Ramos, 2020, Stewart, 2018, Thomassen Hammerstad et al., 2020, Federici and Soddu, 2020, Hoffman-Andrews, 2017), both in developed (Dwarte et al., 2019) and low- and middle-income countries such as India (Tekola-Ayele and Rotimi, 2015). These results can often be misinterpreted by healthcare professionals and patients, leading to unnecessary interventions and psychological stress for patients and families (Donohue et al., 2021). Informing on secondary and clinically actionable incidental findings unrelated to the primary indication is important to prepare them for such possibilities. Genetic counselors in pediatric clinics, hence, play a critical role in the interpretation of results and guidance of families, reiterating the importance of pre- and post-test genetic counseling (Diderich KEM, 2023, Michaela Cormack, 2024). Post-genomic era genetic counseling challenges need to be addressed within a framework (Stewart, 2018), mindful of the clinical and personal indications of the patients (McGlynn and Langfelder-Schwind, 2020, Menke et al., 2021). This paper focuses on patient groups with ophthalmic, neurodevelopmental, and other pediatric-onset conditions, highlighting their pre- and post-test genetic counseling.\u003c/p\u003e\u003c/div\u003e\n\n\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe retrospectively studied subjects with pediatric-onset conditions referred to us for genetic counseling between January 2018 and June 2024 at our clinics in GenVams Trust, Chennai, and Nishta Integrated Neurodevelopment Centre, Chennai, India. The subjects were categorized into 3 groups based on the pediatric subspecialty referrals: pediatric-onset ophthalmic concerns, NDDs, and other pediatric referrals that did not belong to the previous two subspecialties. Three-generation pedigrees and detailed clinical and family medical histories were ascertained. Non-directive pre-test genetic counseling addressed genomic testing as per the clinical indication (Savatt and Myers, 2021) (Bateman and Silva, 2013) (Ewans et al., 2018), diagnostic outcomes (detection of a causative variant, VUS, or uninformative results), management, options of estimation of recurrence for future pregnancies in the event of a confirmed genetic diagnosis, the possibility of secondary and clinically actionable incidental findings, and scope of detection of genomic variations in the tests opted for. We explained that in the absence of any genomic variant or detection of uncertain variants, additional tests could be considered, if applicable, as functional assays to assess VUS are not always possible or feasible in a diagnostic lab (Miranda Durkie, 2024). Ophthalmic investigations comprised electroretinography (ERG), optical coherence tomography (OCT), fundus imaging, visual field test, and best corrected visual acuity (BCVA), as verified by the referring ophthalmologists (SM). Subjects with NDDs and other pediatric concerns underwent neurodevelopmental assessments by developmental paediatrician and neonatologists (SS and MJ) and metabolic (enzyme analysis using tandem mass spectroscopy and gas chromatography), haematological, and imaging studies per the individual requirements. Genetic testing was outsourced to genomics laboratories that are CLIA (Clinical Laboratory Improvement Amendments) compliant, and CAP (College of American Pathologists) accredited. This comprised of karyotyping (G-banding at 450 band resolution), NGS-based whole exome sequencing (WES), clinical exome sequencing (CES, sequencing of approximately 8000 genes curated for commonly prevalent clinical genetic conditions) (Campbell et al., 2023), or multi-gene panels (list of genes provided in supplementary data), chromosomal microarray (CMA), multiplex ligation dependant probe amplification (MLPA), and fragile-X syndrome TP-PCR analysis, as specified in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Parental testing used the Sanger sequencing method when performed in cases of suspected compound heterozygosity for autosomal recessive (AR) variants. The choice of genomic tests was dependent on the autonomy of the affected family and, particularly, their socioeconomic status. Based on the genomic results with variants classified as per the ACMG criteria (Richards et al., 2015) the subjects were further categorised into three groups: (i) those with a confirmed genetic diagnosis with pathogenic (P) or likely pathogenic (LP) variants, (ii) those with a combination of P/LP variants with VUS, and (iii) those who had only VUSs or nil variants reported. Post-test genetic counseling was focused on interpreting the genetic results following the indication for referral. Clinical details were cross-checked by the clinicians against the identified variant, and possibilities to continue additional testing (clinical and genetic), if indicated, were discussed with the families.\u003c/p\u003e\u003cp\u003eTable 1: Distribution of subjects according to their clinical presentation and genetic test results\u0026nbsp;\u003c/p\u003e\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal N=38\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOphthalmology group (N=13)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNDD group (N=18)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOther pediatric group (N=7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOnly P/LP\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN=11 (84.6%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN=8 (44.4%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN=3 (43%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003eSubjects:9,10,11,12,13,14,15,18,19, 24,26\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eSubjects: 1,3, 4,5, 8,17, 29, 38\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003eSubjects: 2, 6, 16\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP/LP with VUS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN=1 (7.7%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN=2 (11.2%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN=2 (28.5%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003eSubjects: 25\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eSubjects: 22, 23\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003eSubjects: 20, 21\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOnly VUS/ no genetic result\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN=1 (7.7%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN=8 (44.4%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN=2 (28.5%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003eSubjects: 37\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eSubjects: 7, 28, 30, 31, 32, 34, 35, 36\u003c/p\u003e\n \u003c/td\u003e\u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003eSubjects: 27, 33\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003cp\u003e\u003cem\u003eLegend: N-number of subjects, P-pathogenic, LP-Likely pathogenic, VUS-variant of uncertain significance, NDD- NDD-neurodevelopmental disorder\u003c/em\u003e\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDemographic, clinical, and molecular genetic details of the subjects\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"11\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAge at referral/ Gender\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eParental Consanguinity/ Endogamy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eClinical indication\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGenetic test\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eGene/ Chromosome\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eVariant\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eZygosity / Inheritance pattern of the reported gene\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eDiagnosis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePrediction tools results\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eLaboratory reported classification as per ACMG criteria\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1year 8months /Male\u003c/p\u003e\u003cp\u003e(deceased)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCongestive hepatomegaly, pallor, congenital hypertrichosis, microcytic hypochromic anemia, pulmonary hypertension, mild cardiomegaly, developmental delay\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eABCC9\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.3461G \u0026gt; A p.Arg1154Gln\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/ AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCantu syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDamaging (SIFT, LRT, MutationTaster2), Probably damaging (Polyphen-2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eLikely pathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 month/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNewborn screen positive for Immunoreactive trypsinogen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eCFTR\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.327T \u0026gt; A\u003c/p\u003e\u003cp\u003ep.Tyr109Ter\u003c/p\u003e\u003cp\u003ec.3353C \u0026gt; T\u003c/p\u003e\u003cp\u003ep.Ser1118Phe\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCompound heterozygous/ AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCystic fibrosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDamaging (SIFT, LRT, MutationTaster2), Probably damaging (Polyphen-2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 years/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGlobal developmental delay\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003cp\u003eCMA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eChr. 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e5p15.33p13.3 deletion\u003c/p\u003e\u003cp\u003earr[hg19]5p15.33p13.3\u003c/p\u003e\u003cp\u003e(113,577 − 31,150.935)x1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/ AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCri-du-chat syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 years/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutism spectrum disorder\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003cp\u003e\u003cem\u003eFMR1\u003c/em\u003e TP-PCR (normal range of CGG repeats)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eSETD1A\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.4175G \u0026gt; A, p.Arg1392His\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/ AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNeurodevelopmental disorder with speech impairment and dysmorphic facies\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDeleterious (SIFT), Damaging (Polyphen-2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eLikely pathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 year/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2nd -degree consanguinity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDelayed motor milestones, facial dysmorphisms\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eCUL7\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.4651C \u0026gt; T \u003c/p\u003e\u003cp\u003ep.Gln1551Ter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHomozygous/ AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e3-M syndrome 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeonate (deceased)/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3rd -degree consanguinity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCongenital arthrogryposis, myoclonus seizures\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eBRAT1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.1313_1314del\u003c/p\u003e\u003cp\u003e(p.Gln438ArgfsTer51)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHomozygous/ AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNeonatal rigidity and multifocal seizure syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDamaging (MutationTaster2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 years/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutism spectrum disorder with seizures\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eSETD1B\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.273 + 2T \u0026gt; C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSplice AI 0.13 (Benign)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 years/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3rd -degree consanguinity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGlobal developmental delay\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eKMT2D\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.14002dup p.Thr4668AsnfsTer2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/ AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eKabuki syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 years/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRetinitis Pigmentosa\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNGS-based gene panel\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eCRX\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.585C/A\u003c/p\u003e\u003cp\u003ep. Tyr195Ter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/ AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eRetinitis Pigmentosa\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 years/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRetinitis Pigmentosa\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eCDH23\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.6514del p.Glu2173SerfsTer9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHomozygous/ AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eUsher syndrome type 1D\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDamaging (MutationTaster2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30 years/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2nd -degree consanguinity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRetinitis Pigmentosa, intellectual disability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNGS-based gene panel\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eC8orf37/3\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.258delA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHomozygous/ AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eBardet-Biedl syndrome-21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 years/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAlbinism with congenital speech and hearing impairment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eMITF\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.935G \u0026gt; G/T\u003c/p\u003e\u003cp\u003ep.Arg318Ile\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/ AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWaardenburg syndrome type 2A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDamaging (MutationTaster2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eLikely pathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 years/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSquint, retino-choroidal coloboma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCMA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eChr. 15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003earr[GRCh37] 15q13.2q13.3(31098691_32914239)x1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/ AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMicrodeletion 15q13.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eLikely pathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15 years/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSpeech delay, behavioural issue, cafe au lait macules, Lisch nodules\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eNF1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.6855C \u0026gt; A p.Tyr2285Ter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/ AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNeurofibromatosis − 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDamaging (MutationTaster2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 years/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNight blindness, retinitis pigmentosa\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eRPGR\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.469 + 1G \u0026gt; A 5' splice site\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHemizygous/ XLR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eRetinitis Pigmentosa-3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 years/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHip displacement\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eCOL2A1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.3508G \u0026gt; A p.Gly1170Ser\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/ AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAvascular necrosis of the femoral head\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDamaging (SIFT, LRT, MutationTaster2), Probably damaging (Polyphen-2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 years/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3rd -degree consanguinity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDevelopmental delay, severe hearing loss, corpus callosum thinning\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNGS-based gene panel\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eSGSH\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.544C \u0026gt; T p.Arg182Cys\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHomozygous/ AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMucopolysaccharidosis 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDamaging (SIFT, LRT, MutationTaster2), Probably damaging (Polyphen-2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 years/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRetinal degeneration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNGS-based gene panel\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eLCAS\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.1151delC\u003c/p\u003e\u003cp\u003ep.Pro384GlnfsTer18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHomozygous/ AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eLeber congenital amaurosis-5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDamaging (MutationTaster2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17 years/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003edifficulty in night vision, retinitis pigmentosa\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eEYS\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.6714del p.Ile2239SerfsTer17 c.1211dup p.Asn404LysfsTer3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCompound heterozygous/ AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eRetinitis Pigmentosa 25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDamaging (MutationTaster2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eSubject 20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e14 years/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003ePtosis, astigmatism, migraine (unspecified), muscle fatigue, b/l sensorineural hearing loss, pigmentary retinopathy, diplopia, syncope, bradycardia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003eUSH2A\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.8167C \u0026gt; T\u003c/p\u003e\u003cp\u003ep.Arg2723*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eBoth disease-causing (Mutation Taster)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.8924T \u0026gt; G\u003c/p\u003e\u003cp\u003ep.Ile2975Ser\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/AR \u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eSubject 21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e1 year/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eAfebrile seizure, parotid hemangioma, hypotonia, gas chromatography showed elevated 4-hydroxybutyric acid, glycolic acid, and 2-deoxytetronic acid.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003eALDH5A1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.1226G \u0026gt; A\u003c/p\u003e\u003cp\u003ep.Gly409Asp\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eCompound heterozygous\u003c/p\u003e\u003cp\u003e/ AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.274G \u0026gt; T\u003c/p\u003e\u003cp\u003ep.Asp92Tyr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eSubject 22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e3 years/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e3rd -degree consanguinity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eGlobal developmental delay\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003cp\u003eMitochondrial genome sequencing (No SNV and CNV detected)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cem\u003eSDHA\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.1534C \u0026gt; T\u003c/p\u003e\u003cp\u003ep.Arg512Ter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eCompound heterozygous\u003c/p\u003e\u003cp\u003e/ AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.1337T \u0026gt; C p.Val446Ala\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.1346C \u0026gt; T p.Ala449Val\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eSubject 23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e8 years/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003enon-consanguineous, non-endogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eIntellectual disability, speech and language delay, Autism spectrum disorder\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eLINS1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.1945C \u0026gt; T p.Gln649*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous /AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eMedium severity (REVEL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eFBXW7\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.118G \u0026gt; A p.Glu40Lys\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDeleterious (SIFT) Damaging (MutationTaster)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 years/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSquint, sensitivity to light, retinitis pigmentosa\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eIFT172\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.3850C \u0026gt; C/T p.Arg128Ter\u003c/p\u003e\u003cp\u003ec.4775T \u0026gt; T/C p.Met1592Thr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCompound heterozygous/ AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eRetinitis Pigmentosa 71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDamaging (LRT, MutationTaster2),\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eLikely pathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eSubject 25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e16 years/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eMacular dystrophy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eNGS-based gene panel\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003eABCA4\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec. 5371dupG p.Ala1791GlyfsTer9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eCompound heterozygous\u003c/p\u003e\u003cp\u003e/ AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eDamaging (MutationTaster2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.6193G \u0026gt; C p.Asp2065His\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 years/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-consanguineous, non-endogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRetinitis pigmentosa\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNGS-based gene panel\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003ePROM1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec. 1632G \u0026gt; T p.Gly544=\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHomozygous/AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eRetinitis Pigmentosa − 41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eLikely Pathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 days (deceased)/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFailure to thrive, lactic acidosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eC1QBP\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.478-7T \u0026gt; G\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHomozygous/ AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 years/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutism spectrum disorder with cafe au lait macules\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eUBE3A\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.1255C \u0026gt; G\u003c/p\u003e\u003cp\u003ep.Pro419Ala\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/ AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eSubject 29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e7 years/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eIntellectual disability with Autism spectrum condition\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003eVWF\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003ec.2447G \u0026gt; A p.Arg816Gln\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eHeterozygous/AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eVon-Willebrand disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eLikely pathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCMA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eChr.12\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003earr[GRCh37] 12p13.33\u003c/p\u003e\u003cp\u003e(173786_316360)x1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e12p13.33 Microdeletion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eSubject 30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e5 months/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e3rd -degree consanguinity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eHypotonia, floppy infant, developmental delay\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMLPA (\u003cem\u003eSMN1 \u0026amp; SMN2\u003c/em\u003e gene)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eSMN1\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eSMN2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eExon7 copy no.3\u003c/p\u003e\u003cp\u003eExon 8 copy no.3\u003c/p\u003e\u003cp\u003eExon 7 copy no.1\u003c/p\u003e\u003cp\u003eExon 8 copy no.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eTNNT1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.649T \u0026gt; A\u003c/p\u003e\u003cp\u003ep.Cys217Ser\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHomozygous/AR \u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eBenign (PolyPhen2, MutationTaster2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eSubject 31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e8 years/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eIntellectual disability, moderate, thin corpus callosum, cerebral white matter hypoplasia, apneic episodes, seizures, facial dysmorphism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003cp\u003eMS-MLPA (Prader-Willi and Angelman syndrome, negative)\u003c/p\u003e\u003cp\u003e\u003cem\u003eFMRI\u003c/em\u003e gene TP-PCR (negative)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eKNL1 \u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.3493G \u0026gt; A\u003c/p\u003e\u003cp\u003ep.Glu1165Lys\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHomozygous/AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eTolerated(SIFT), Benign (Polyphen2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eSYNJ1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.2125C \u0026gt; T\u003c/p\u003e\u003cp\u003ep.Arg709*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eTolerated SIFT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eCFTR\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.2756A \u0026gt; G\u003c/p\u003e\u003cp\u003ep.Tyr919Cys\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/AR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDamaging (Polyphen2, MutationTaster2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 years/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutism spectrum disorder\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003cp\u003e\u003cem\u003eFMRI\u003c/em\u003e gene TP-PCR (negative)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNo variant detected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 years/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eB/l Sensorineural hearing loss\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eTRRAP\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.5146G \u0026gt; A\u003c/p\u003e\u003cp\u003ep.Gly1716Arg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/ AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDamaging (SIFT, MutationTaster2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eSubject 34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e2 years/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eGlobal developmental delay, autism spectrum disorder, cafe au lait macules,\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eSCAF4\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.3246G \u0026gt; C; p.Glu1082Asp\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDamaging -SIFT, MutationTaster2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eCNTNAP2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.2956G \u0026gt; A; p.Gly986Ser\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous /AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDamaging- SIFT, MutationTaster2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003ePNPT1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.716A \u0026gt; C; p.Gln239Pro\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous /AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eTolerated SIFT, Damaging MutationTaster2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 years/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMotor developmental delay, mild dysmorphisms, Kidney small with increased echogenicity,\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eSMC1A\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.1847C \u0026gt; T p.Ala616Val\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous / XLD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDamaging (SIFT, LRT, MutationTaster2, Polyphen-2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 year/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3rd -degree consanguinity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGlobal developmental delay\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003cp\u003eCMA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNo variant detected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubject 37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 years/ Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRetinoblastoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCES\u003c/p\u003e\u003cp\u003eCMA\u003c/p\u003e\u003cp\u003eMLPA (\u003cem\u003eRB1\u003c/em\u003e gene)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNo variants reported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eSubject 38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e2 years/ Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eEndogamous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eGlobal developmental delay\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCMA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncreased ROH in chromosomes 5q and 16q\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eARID2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.1075delG, p.Val359Leufs*5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHeterozygous/ AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCoffin-Siris syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eLikely Pathogenic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"11\"\u003e\u003cem\u003eLegend: CES- Clinical Exome Sequencing, WES- Whole Exome Sequencing, CMA- Chromosomal Microarray, MS-MLPA- Methylation-specific Multiplex Ligation dependant Probe Amplification, MLPA- Multiplex Ligation dependant Probe Amplification, TP-PCR- Triplet Primed Polymerase Chain Reaction, AD- Autosomal Dominant, AR- Autosomal Recessive, XLD- X-Linked Dominant, XLR- X-linked Recessive, NGS- Next-Generation Sequencing, SNV- Single Nucleotide Variant, CNV- Copy Number Variant, NA- Not Available, ROH- Regions Of Homozygosity, VUS- Variant of Uncertain Significance\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 38 subjects of Asian Indian ethnicity with paediatric-onset referrals who underwent genetic counseling and testing were reviewed (Table\u0026nbsp;1). The clinical symptoms and genomic results of all 38 subjects are provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Thirteen subjects had ophthalmic conditions such as RP, macular dystrophy, retinoblastoma, and albinism with deaf mutism. Eighteen subjects had clinical manifestations of NDDs, and their symptoms comprised speech delays, reduced response to name calls, lack of eye contact, receptive language delays, expressive language delays, delayed motor milestones, restricted and repetitive behaviors, social communication deficits, and hyperactivity. Based on the developmental pediatrician\u0026rsquo;s assessment, clinical diagnoses comprised either ASD, ADHD, ID, or GDDs. Seven had other pediatric indications (orthopedic conditions, hearing impairment, and inborn error of metabolism) that did not fall under ophthalmic or NDD indications.\u003c/p\u003e\u003cp\u003eAmongst the ophthalmic subjects, 84.6% (11/13) carried pathogenic/likely pathogenic (P/LP) variants in candidate genes that could explain the clinical phenotype and mode of inheritance. In subjects 9, 10, 11, 12, 13, 14, 15, 18, 19, 24, and 26 (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e), a syndromic diagnosis such as Usher syndrome, Bardet-Biedl syndrome, Waardenburg syndrome type 2A, microdeletion 15q13.2, neurofibromatosis type 1, and Leber congenital amaurosis was confirmed. In 7.7% (1/13) of ophthalmic subjects, genetic results had a P/LP variant and VUS combination in the same gene involved in AR disease, and 7.7% (1/13) had no molecular genetic variants identified. In the NDD group, 44.4% (8/18) had P/LP variants in candidate genes that could explain the clinical phenotype and mode of inheritance. Subjects 1, 3, 4, 5, 8, 17, 29, and 38 had genetic diagnoses of Cantu syndrome, Cri-du-chat syndrome, neurodevelopmental disorder with speech and dysmorphic facies, 3-M syndrome, Kabuki syndrome, mucopolysaccharidosis type 3, 12p13.33 microdeletion syndrome, and Coffin-Siris syndrome. 11.1% (2/18) had combinations of P/LP variants and VUS in the same gene involved in AR disease, and in 44.4% (8/18), only VUS or no molecular genetic variants were identified. In subjects with other pediatric conditions, 42.8% (3/7) had a genetic diagnosis established with P/LP variants in genes explaining the clinical phenotype. Subjects 2, 6, and 16 were diagnosed with cystic fibrosis, neonatal rigidity, and multifocal seizure syndrome and avascular necrosis, respectively. In 28.5% (2/7), there were combinations of P/LP variants and VUS in the same gene involved in AR disease, and in 28.5% (2/7), there was no genetic diagnosis confirmed.\u003c/p\u003e\u003cp\u003e\u003cem\u003eSecondary and clinically actionable incidental findings\u003c/em\u003e\u003c/p\u003e\u003cp\u003eAs per recommendations for reporting secondary and clinically actionable incidental findings (Miller et al., 2021), variants were reported in 2 subjects. Subject 20 had a homozygous pathogenic variant associated with partial biotinidase deficiency in the \u003cem\u003eBTD\u003c/em\u003e gene (c.1336G\u0026thinsp;\u0026gt;\u0026thinsp;C, p.Asp446His). Interestingly, the primary diagnosis was yet ambiguous (parents were counseled regarding further testing for segregation of the \u003cem\u003eUSH2A\u003c/em\u003e variants by Sanger sequencing and testing for mitochondrial deletions in the proband) alongside medications to address his biotinidase deficiency prescribed by our clinician (MJ). Subject 29 (primary diagnosis of 12p13.3 microdeletion syndrome) was identified with a heterozygous likely pathogenic variant in the VWF (von Willebrand factor) gene (exon19: c.2447G\u0026thinsp;\u0026gt;\u0026thinsp;A, p.Arg816Gln) associated with autosomal dominant (AD) von Willebrand disease. She was further referred for a hematological follow-up to direct appropriate prophylaxis and management. Both findings were explained during post-test genetic counseling and confirmed by the clinicians in our group (MJ and SS). We provide below the clinical presentations and genetic output of six representative subjects (indicated by arrows), two from each category, with their pedigrees depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Post-test genetic counseling for each group is addressed. Pedigree symbols are as per the standardized nomenclature (Bennett et al., 2008).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eOphthalmic group\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eSubject 25\u003c/em\u003e\u003c/p\u003e\u003cp\u003eA 16-year-old female, born of a non-consanguineous marriage with no family history, was clinically diagnosed with macular dystrophy. She reported blurred vision, distant and near, since age 12. Her BCVA was 6/7.5 in both eyes, which declined to 6/18P in the right eye and 6/12P in the left eye with N8 in both eyes over 4 years. Fundus examination revealed normal vessels and discs but a bull's-eye lesion in the macula. Fundus autofluorescence indicated hypoautofluorescence, suggesting retinal pigment epithelium atrophy. OCT revealed the absence of inner and outer retinal layers and a loss of inner and outer segment junction layers. Multifocal ERG recorded reduced central foveal spike and parafoveal responses, suggestive of reduced macular cone photoreceptor function. Her parents opted for an NGS-based retinal degeneration gene panel test that revealed heterozygous variants in the \u003cem\u003eABCA4\u003c/em\u003e gene (pathogenic variant in exon 38: c.5371dupG, p.Ala1791GlyfsTer9 and a VUS in exon 45: c.6193G\u0026thinsp;\u0026gt;\u0026thinsp;C, p.Asp2065His). We counseled the family on parental testing for the phasing of the variants and clinical surveillance for disease progression (Tanna et al., 2017). We informed them that the VUS may likely be reclassified as causative based on additional supportive evidence (Miranda Durkie, 2024) that could substantiate the presence of the pathogenic variants in trans with VUS, as demonstrated previously (Gupta et al., 2023).\u003c/p\u003e\u003cp\u003e\u003cem\u003eSubject 37\u003c/em\u003e\u003c/p\u003e\u003cp\u003eA 9-year-old male child born to non-consanguineous parents with no family history was evaluated for leukocoria at 6 months and diagnosed with bilateral retinoblastoma. Two small-sized tumors were detected in the superonasal and the inferonasal quadrant of the right eye (group A retinoblastoma) (Ancona-Lezama et al., 2020), while a subretinal yellowish-white mass filling the vitreous cavity with retinal detachment (group E retinoblastoma) was observed. A B-scan of the left eye showed high echogenic areas of focal calcification, and brain and orbit computed tomography was suggestive of optic nerve infiltration in the left eye. He underwent left eye enucleation with a primary implant, and the right eye was treated with laser radiation. Histopathology confirmed features of well-differentiated retinoblastoma infiltrating the lamina cribrosa with tumor-free margins of the optic nerve and choroid. He received 4 cycles of adjuvant chemotherapy. The parents were planning another pregnancy and opted for an NGS-based CES. There was no identifiable genetic variant through blood sampling, and the tumor tissue was unavailable for genetic testing; the coverage of the exons of the \u003cem\u003eRB1\u003c/em\u003e gene was 100%. The parents pursued additional genetic testing, such as \u003cem\u003eRB1\u003c/em\u003e gene exon deletion/duplication via MLPA and CMA, to check for copy number variants that returned negative results. As the parents had expectations from the genetic test to help them plan their next pregnancy, we explained that a yet unidentified \u003cem\u003ede novo\u003c/em\u003e mutation is likely responsible for the disease manifestation. The recurrence risk is much lower than in autosomal dominant retinoblastoma, but could be as much as 5% due to germline mosaicism. As no causative variant was found, this cannot be tested prenatally. The parents were counseled on options for early ophthalmic screening for future offspring to prevent low vision, blindness, and other morbid outcomes based on current guidelines (Schaiquevich et al., 2022, Skalet et al., 2018).\u003c/p\u003e\u003cp\u003e\u003cb\u003eNeurodevelopmental disorders (NDDs) group\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eSubject 23\u003c/em\u003e\u003c/p\u003e\u003cp\u003eAn 8-year-old female child born to non-consanguineous parents and with no family history was diagnosed with ASD. The psychological evaluation indicated a developmental and social age equivalent to a 3-year and 8-month level. The parents were planning their next pregnancy and opted for WES for their child. Results revealed a heterozygous likely pathogenic nonsense variant in the \u003cem\u003eLINS1\u003c/em\u003e gene (exon 7: c.1945C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.Gln649*) associated with AR intellectual developmental disorder, but no second causative variant was found. This could imply the possibility of a second mutation yet unidentified or an incidental carrier status for an autosomal recessive disorder and warrants additional screening, such as for copy number variants. A heterozygous missense VUS in the \u003cem\u003eFBXW7\u003c/em\u003e gene (exon 4: c.118G\u0026thinsp;\u0026gt;\u0026thinsp;A, p.Glu40Lys) was additionally detected. The gene is associated with AD developmental delay with hypotonia and language impairment. The heterozygous VUS in the \u003cem\u003eFBXW7\u003c/em\u003e gene could be \u003cem\u003ede novo\u003c/em\u003e, and parental testing is needed to confirm the origin (Miranda Durkie, 2024). The parents were counseled regarding these options; however, they did not proceed with testing owing to the high costs incurred and conveyed that they would reconsider this over time.\u003c/p\u003e\u003cp\u003e\u003cem\u003eSubject 36\u003c/em\u003e\u003c/p\u003e\u003cp\u003eA 1-year-4-month-old female child born to 3rd-degree consanguineous parents was diagnosed with GDD. Prenatal second-trimester scans showed a fetus with an unossified nasal bone, splaying of the neural arch of the last sacral vertebra, prenasal edema, persistent left superior vena cava, and small fetal size for gestational age. She was delivered via an emergency cesarean section due to fetal distress and meconium-stained liquor. The birth cry was delayed, requiring resuscitation. Facial dysmorphism included low-set ears, hypertelorism, synorphys, high-arched palate, long philtrum, microcephaly, low hairline, retrognathia, and hemangioma on the spine. She had acyanotic congenital heart disease with pseudostrabismus. The magnetic resonance imaging (MRI) brain suggested periventricular leukomalacia as a hypoxic-ischemic sequelae. The parents sought an accurate diagnosis for improved management beyond current physiotherapy and speech-swallow therapy. Genetic testing that comprised CMA, WES, and karyotyping was negative for any variants. Addressing such possibilities during pre-test genetic counseling was instrumental for the parents to cope with the negative results of expensive tests. Currently, she is on clinical surveillance and advised a periodic reanalysis of results.\u003c/p\u003e\u003cp\u003e\u003cb\u003eOther Paediatric Conditions Group\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eSubject 21\u003c/em\u003e\u003c/p\u003e\u003cp\u003eA 4-month-old female child, born to non-consanguineous, endogamous parents, had no prior family history and presented with infantile parotid hemangioma and unprovoked seizures from 1 month of age. She had hypotonia, complete head lag in the pull-to-sit position, and plagiocephaly with a flattened right occipital bone. Hammersmith's infant neurological examination score was 40/78, with a minimum score of 67 considered normal between ages 3\u0026ndash;6 months (Romeo et al., 2022). Auditory and ophthalmic examinations, MRI, and 3D computed tomography of the brain were normal. Metabolic screening via gas chromatography showed increased levels of 4-hydroxybutyric acid-2 (3.46 MoM/NMT 1.87) and 2-deoxytetronic acid-3 (1.59 MoM/NMT 0.91), both of which were confirmed on repeat testing. Concerned about the diagnosis and recurrence in future pregnancies, the parents opted for trio-based WES. The child had heterozygous variants in the \u003cem\u003eALDH5A1\u003c/em\u003e gene (a pathogenic exon 8: c.1226G\u0026thinsp;\u0026gt;\u0026thinsp;A, p.Gly409Asp variant and a VUS in exon 1: c.274G\u0026thinsp;\u0026gt;\u0026thinsp;T, p.Asp92Tyr). Parental exome sequencing established the compound heterozygosity in the child. The \u003cem\u003eALDH5A1\u003c/em\u003e gene is implicated in autosomal recessive succinic semialdehyde dehydrogenase deficiency (OMIM#271980), also called 4-hydroxybutyric aciduria, which is an ultra-rare monogenic disorder of the gamma-aminobutyric acid (GABA) metabolism that usually exhibits clinical heterogeneity. Affected persons receive symptomatic management and therapy for neurobehavioral symptoms (Didiasova et al., 2020). This subject had elevated levels of 4-hydroxybutyric acid-2. This endorsed a biochemical diagnosis, and the presence of compound heterozygous variants (pathogenic and VUS) in the \u003cem\u003eALDH5A1\u003c/em\u003e gene substantiated an etiologic linkage, as co-segregation too was established in this case. This was explained to the parents, and we discussed options to re-analyze the VUS and how these linked single-nucleotide variants could impact future reproductive choices (prenatal and pre-implantation genetic testing).\u003c/p\u003e\u003cp\u003e\u003cem\u003eSubject 16\u003c/em\u003e\u003c/p\u003e\u003cp\u003eAn 11-year-old male child, born of a non-consanguineous marriage, presented with symptoms of gait abnormality. The X-ray of the pelvis was suggestive of bilateral avascular necrosis, and the MRI of the pelvis showed features of bilateral Perthes disease. Family pedigree revealed multiple members similarly affected on the proband\u0026rsquo;s paternal side (father, grandfather, uncle, cousins, and great-grandmother), with three of them having undergone hip-replacement surgeries. The parents chose to proceed with CES for the subject, which revealed the presence of a heterozygous pathogenic variant in the \u003cem\u003eCOL2A1\u003c/em\u003e gene (exon 50: c.3508G\u0026thinsp;\u0026gt;\u0026thinsp;A, p.Gly1170Ser), confirming a diagnosis of autosomal dominant avascular necrosis of the femoral head (OMIM#608805). The clinical presentation, family pedigree, and molecular genetic findings in this subject were in synchrony, which helped to counsel the family towards considering molecular confirmation of other similarly affected members and advise those willing on risk estimation.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e\u003cem\u003eGenetic diagnosis and counseling between the groups\u003c/em\u003e\u003c/p\u003e\u003cp\u003eIn our study, we retrospectively analyzed the clinical presentations of 38 subjects with genetic test findings in the context of genetic counseling. It was seen that 84.6% of subjects belonging to ophthalmic, 44.4% to NDDs, and 42.8% to other pediatric conditions had a confirmed molecular genetic diagnosis established with P/LP variants, matching the clinical symptoms. Ophthalmic conditions have a higher success rate in clinical and genetic diagnoses as they are predominantly monogenic. In our study, 44.4% of NDD subjects remained with uncertain/uninformative results against 7.7% and 28.5% in the ophthalmic and other-pediatric conditions groups, respectively. A meta-analysis published recently (Britten-Jones et al., 2023) showed that NGS aided in an accurate diagnosis in 61.3% of persons with inherited retinal diseases. The diagnostic output of genetic tests for NDDs is variable; CMA (9\u0026ndash;13%), exome sequencing with re-analysis (26\u0026ndash;30%), whole genome sequencing (WGS) (40\u0026ndash;45%) (Lee and Nelson, 2020), and up to 2.5% for fragile-X syndrome testing of males with ID (Carter et al., 2023b). The diagnostic yield is 21\u0026ndash;80% for all pediatric conditions pooled (Lee, 2023), wherein subspecialties of ophthalmology and inborn errors of metabolism were amongst the highest. Ambiguity in genetic results is common in the post-genomic era (Newson et al., 2016), with clinical and genetic heterogeneity present in different pediatric sub-specialties.\u003c/p\u003e\u003cp\u003eAdvancements in genetic diagnostic techniques have transformed the speed and accuracy of diagnosis in many individuals and families who never knew the cause of their condition for years (Stark et al., 2016a). This was evident as seen in subject 16, whose molecular diagnosis was missed across three generations. In this family, molecular confirmation with post-genomic techniques was achieved within days, as opposed to waiting for decades. Avascular necrosis of the femoral head is caused by the disruption of blood supply to the proximal femur, resulting in osteocyte death. It can result from traumatic (fracture, hip dislocation) or non-traumatic causes (corticosteroid use, alcoholism, sickle cell disease, bone marrow transplant, etc.), with Legg-Calve-Perthes disease being the most common cause when it occurs in children. It shares the same histopathological feature of osteonecrosis but is restricted to the hip joints and can be caused by highly penetrant variants in the \u003cem\u003eCOL2A1\u003c/em\u003e gene. With a variable age of onset, prior knowledge of a person\u0026rsquo;s risk aids in better management and prognosis, and this was communicated to the family, too (Asadollahi et al., 2021, Chen et al., 2004).\u003c/p\u003e\u003cp\u003e\u003cem\u003eGenetic counseling in uncertain and uninformative results\u003c/em\u003e\u003c/p\u003e\u003cp\u003eGenetic counselors' role in delivering information regarding outcomes of genetic tests to families in an understandable manner is critical in this post-genomic era, as it facilitates an informed decision to pursue genetic testing based on the clinical condition a child presents with. Uncertain and uninformative results from genetic testing carry with them the prior responsibility of preparing families for such a possibility during pre-test genetic counseling to effectively communicate and help parents cope with such results (Thomassen Hammerstad et al., 2020, Bartley et al., 2020). The possibility of such results varies and could depend on whether the condition is predominantly monogenic or multifactorial in etiology. Variants are classified based on current knowledge of their disease associations, and in laboratory practice, VUSs are reported as part of genetic results when there is an opportunity to explore their role in disease manifestation, as delineated by the Association for Clinical Genomic Science (Miranda Durkie, 2024). Gathering additional evidence could allow reclassification. This could be parental genetic testing to determine if a variant is \u003cem\u003ede novo\u003c/em\u003e, to confirm \u003cem\u003ecis\u003c/em\u003e or \u003cem\u003etrans\u003c/em\u003e phasing of heterozygote variants for a suspected recessive condition, testing affected relatives to derive co-segregation, clinical investigations for phenotypic specificity, or performing functional studies (Miranda Durkie, 2024). VUSs must be treated with caution in the diagnostic journey of pediatric conditions, as the patient's families often bear the burden of such an ambiguous result (Li et al., 2019). In genetic counseling, they are interpreted based on whether they are reported in isolation or in conjunction with other P/LP variants (Miranda Durkie, 2024), phenotype matches, etc., as discussed below.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eSubject 25 had a clinical diagnosis of macular dystrophy, with a combination of a pathogenic variant with a VUS in the \u003cem\u003eABCA4\u003c/em\u003e gene. The \u003cem\u003eABCA4\u003c/em\u003e gene, apart from other retinal dystrophies, is also implicated in autosomal recessive Stargardt disease and presents in childhood with variable disease manifestations. In instances of VUSs in combination with a P/LP variant for a gene associated with autosomal recessive inheritance, parental segregation can be useful to gather evidence for reclassification, as was conveyed to the family.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eSimilar results were seen in subject 21, with a suspected inborn error of metabolism and a combination of a pathogenic variant and VUS in the \u003cem\u003eALDH5A1\u003c/em\u003e gene. In this family, the parents chose trio WES, and the variants were found to be in \u003cem\u003etrans\u003c/em\u003e, with the metabolic investigations clinically supportive of a causative diagnosis.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eSubject 37 had bilateral retinoblastoma with no genetic variant identified after three different genetic tests were performed. Retinoblastomas are one of the most highly curable pediatric neoplasms, with a disease-free survival exceeding 90% (Schaiquevich et al., 2022, Kaliki et al., 2023). While the genetic test results were uninformative, the clinical diagnosis was unambiguous. In this family with no prior history, risk estimation for future pregnancies followed current guidelines (Skalet et al., 2018).\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eSubject 36, clinically diagnosed with GDD, was similarly left with no conclusive results after having performed three genetic tests. As per current estimates, approximately 50% of patients with NDDs remain undiagnosed for causative genomic variants. Here, too, the parents went as far as they could, out of their will to identify the root cause of their child\u0026rsquo;s condition. An uninformative result impacts achieving a diagnosis and downstream management opportunities. Periodic reanalysis may provide answers when improved bioinformatics and the discovery of new genes are available over time (Stark et al., 2019). Genetic counseling (pre- and post-test) hence becomes crucial in families with uninformative results, preparing them for the journey ahead (Fonda Allen et al., 2016, Cormack et al., 2024).\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eGenetic counselors facilitate decision-making and do not make decisions themselves when it comes to genetic testing. Families have multiple considerations, such as how the diagnosis can change management, how much the test costs, possible results of the tests, etc., when they make their choice to test (or not) (Stein et al., 2018). Subject 23 was diagnosed with ASD and had a heterozygous pathogenic variant in the \u003cem\u003eLINS1\u003c/em\u003e gene with no additional variant detected. The option of tests that could detect copy number changes was discussed, but the parents chose to defer their decision to pursue additional testing, with cost consideration being a primary reason. The cost to sequence the entire human genome has drastically reduced from US\u003cspan\u003e$\u003c/span\u003e300\u0026nbsp;million when the initial draft was published to the current value of less than US\u003cspan\u003e$\u003c/span\u003e1000 (Hayden, 2014). In our outsourced laboratories, WES costs around US\u003cspan\u003e$\u003c/span\u003e238.15 (INR 20,000; 1 USD on September 2024\u0026thinsp;=\u0026thinsp;INR 83.98). Even so, genetic testing is not yet popular with families, as the cost in low- and middle-income countries is still high (Zhong et al., 2021, Nahar et al., 2013). Families of children with NDDs often face severe caregiver fatigue and financial burden owing to the high cost of rehabilitation therapies (Maridal et al., 2021). Also, the utility of genetic testing is perceived differently (2015), and in Asian countries such as India, the authority to make decisions, for healthcare included, can rest upon the opinions of individuals up to the immediate or extended family (Weil, 2001) (Young et al., 2021).\u003c/p\u003e\u003cp\u003e\u003cem\u003eGenetic counseling for secondary and clinically actionable incidental findings\u003c/em\u003e\u003c/p\u003e\u003cp\u003eFamilies must be educated during pre-test genetic counseling on possible reporting of secondary and incidental findings resulting from exome sequencing. As per the policy statement of the ACMG, laboratories can disclose variants in genes that are clinically actionable and secondary findings apart from the primary indication of the test (Miller et al., 2021). Subjects 20 and 29 had secondary and clinically actionable incidental findings reported as part of NGS results, and they were previously aware of such a possibility, which made disclosure and discussion toward clinical management peaceful.\u003c/p\u003e\u003cp\u003eIn our study, genetic testing was opted for by parents on an awareness and socioeconomic basis and was not uniform for all the subjects, a limitation we acknowledge. Trio WES, which can improve the diagnostic rate in NDDs (Gao et al., 2019) was also not performed in all subjects due to socioeconomic or personal reasons. In instances of subjects with either only VUSs or no results, some families chose to proceed with additional testing (for example, parental segregation, exome sequencing, or copy number variant analysis), while some did not. We believe this is a kaleidoscopic view of the incorporation of genetic testing from a socio-economic and cultural perspective. In this era of high-throughput diagnostic technology, a confirmed diagnosis has been possible for many affected individuals with impactful consequences for their families (Ramos, 2020). The role of genetic counselors in the pediatric setting is more pertinent now than ever, as it helps clinicians and parents navigate the uncertainties of genomic results and aids informed decision-making.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe post-genomic era has augmented healthcare delivery at an unprecedented pace with accelerated diagnosis of rare pediatric conditions. On the other hand, a consequence of such high-throughput technology is uncertain and uninformative results, be it in ophthalmic, NDDs, or other pediatric conditions, and variably so. We reiterate that pre- and post-test genetic counseling is crucial to facilitate this understanding to affected individuals and their families and guide them towards informed choices. There are barriers, too, to the adoption of genomic services globally (Zhong et al., 2021), and we believe we are amidst concerted efforts by ophthalmologists, pediatricians, laboratory analysts, allied therapists, nursing practitioners, and genetic counselors to overcome this challenge. Molecular genetic diagnosis through NGS screening has transformed and improved the genetic counseling process, unlike in the pre-genomic era, and continues to expand its footprint in healthcare delivery.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003e\u003cb\u003eConflict of Interest\u003c/b\u003e:\u003c/h2\u003e\u003cp\u003eBrinda Ramanathan, Sunita Mohan, Deepika Karthik Kumar, Sugirdhana Parthiban Ramsait, Meenakshi Jayndhyala, Subramanian Sethuraman, Hubert Smeets, and Govindasamy Kumaramanickavel declare that they have no conflict of interest.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cb\u003eEthics approval\u003c/b\u003e:\u003c/strong\u003e\u003cp\u003e Ethics approval was obtained from M.N. Eye Hospital Private Limited (Reg. No.: ECR/249/Indt/TN/2015/RR-18).\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eB.R., conceptualisation; B.R., D.K.K., and S.P.R., data curation; B.R., formal analysis; B.R., S.M., M.J., and S.S., investigation and methodology; B.R. and S.M., writing original draft; S.S., H.S., and G.K., supervision; B.R., writing review; B.R., editing.All authors reviewed the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003e2015. Clinical utility of genetic and genomic services: a position statement of the American College of Medical Genetics and Genomics. \u003cem\u003eGenet Med,\u003c/em\u003e 17\u003cstrong\u003e,\u003c/strong\u003e 505-7.\u003c/li\u003e\n\u003cli\u003e2017. Prevalence and architecture of de novo mutations in developmental disorders. \u003cem\u003eNature,\u003c/em\u003e 542\u003cstrong\u003e,\u003c/strong\u003e 433-438.\u003c/li\u003e\n\u003cli\u003e2024. 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Mendelian inheritance revisited: dominance and recessiveness in medical genetics. \u003cem\u003eNature Reviews Genetics,\u003c/em\u003e 24\u003cstrong\u003e,\u003c/strong\u003e 442-463.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"genetic counseling, variant of uncertain significance, genetic testing, clinical genetics, pediatric genetic disorders","lastPublishedDoi":"10.21203/rs.3.rs-7063331/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7063331/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eEstablishing a confirmed diagnosis of pediatric-onset genetic conditions has undergone a paradigm shift in the post-genomic era. Consequently, the practice of genetic counseling has also transformed. Clinical and genetic heterogeneities (in monogenic and complex diseases) and variants of uncertain significance (VUS) pose challenges across clinical disciplines. We thus retrospectively analyzed 38 subjects with pediatric-onset conditions who underwent clinical examination, genetic counseling, and testing. The subjects were categorized based on their clinical presentations and genomic screening results (ophthalmic, neurodevelopmental disorders [NDDs], and other pediatric conditions outside the two subspecialties). Among the ophthalmic subjects, 84.6% had confirmed pathogenic/likely pathogenic (P/LP) variants, 7.7% had combinations of P/LP variants and VUS, and 7.7% had no significant molecular genetic variants. In the NDDs group, 44.4% had confirmed P/LP variants, 11.2% had combinations of P/LP variants and VUS, and 44.4% had either only VUSs or uninformative results. In the remaining subjects, 43% carried confirmed (P/LP) variants, 28.5% had a combination of P/LP and VUS, and 28.5% were inconclusive. We discuss the implications of these findings with the subject families and how pre- and post-test genetic counseling aided their informed decision-making. Clinical and genetic heterogeneities present challenges that clinicians and genetic counselors face, differing between monogenic and complex conditions. Genetic counselors should inform patient families of possible outcomes during pre-test and post-test counseling, as it supports informed decision-making. Although VUSs remain the most significant genetic counseling challenge in all three groups, post-genomic era high-throughput technologies have greatly enhanced healthcare delivery.\u003c/p\u003e","manuscriptTitle":"Post-Genomic Era: Critical Role of Genetic Counseling in a Pediatric Clinic","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-14 10:11:17","doi":"10.21203/rs.3.rs-7063331/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bb291f47-fb91-4f51-868d-0996cf2bc370","owner":[],"postedDate":"July 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-17T11:09:15+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-14 10:11:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7063331","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7063331","identity":"rs-7063331","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}