Co-existence of Cohen Syndrome and Pendred Syndrome? Diagnostic Challenges Associated With Presence of Multiple Genomic Variants in the Newborn: A Case Report

Co-existence of Cohen Syndrome and Pendred Syndrome? 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Diagnostic Challenges Associated With Presence of Multiple Genomic Variants in the Newborn: A Case Report Guoxu Li, Yu Mu, Chao Sun, Jie Zheng, Xiaowei Xu, Xiaodan Yan, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-93977/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 Background Cohen syndrome is a multisystem autosomal recessive hereditary disease, which is caused by variants of the VPS13B gene. The clinical manifestations include characteristic facial features, microcephaly, trunk obesity and mental retardation. The SLC26A4 gene encodes an anion transporter called Pendrin, the variants of SLC26A4 lead to deafness, Pendred syndrome and enlarged vestibular aqueduct. We presence a case of multiple genetic homozygous variants of SLC26A4 and VPS13B. Case presentation In this study, we described a case of a 65-day-old female infant presenting with hearing loss and poor feeding. The deafness gene screening before admission showed that the patient carried homozygous c.919-2A>G variation of SLC26A4 gene. The symptoms of the patient did not improve significantly after a period of targeted treatment, then the possibility of genetic diseases was considered after consultation with the different departments. Whole exome sequencing was performed, and homozygous splicing variants in intron 38 (c.6940+1G>T) of VPS13B and that in intron 7 (c.919-2A>G) of SLC26A4 were identified. Later, the parent was proved as the carriers of VPS13B and SLC26A4 heterozygous variations by Sanger sequencing. Conclusions Presence of multiple genetic homozygous variants of SLC26A4 and VPS13B , it is difficult to make an early diagnosis due to early atypical symptoms. Final diagnosis depends on whole exome sequencing which plays an important role in early diagnosis of intractable neonatal cases. Pediatrics Cohen syndrome VPS13B gene Pendred syndrome SLC26A4 gene Genetic deafness Figures Figure 1 Figure 2 Background Cohen syndrome (CS; OMIM#216550) was first described in 1968 with the name of the patient’s name for Pepper syndrome[1]. Then it was confirmed by Cohen and the colleagues in 1973 and named as CS[2]. CS is an autosomal recessive genetic multisystem disease. The clinical manifestations of different ethnic groups have been proved to be different, the classical manifestations include characteristic facial features, microcephaly, trunk obesity, mental retardation, progressive retinopathy and intermittent congenital neutropenia, etc[1, 2]. VPS13B gene was cloned in 2004, the germline variation of VPS13B gene on chromosome 8q22.2 is considered to be the hereditary cause of CS[3]. VPS13B contains 66 exons, spans a genomic region of approximately 864 kb[3, 4]. It mainly encodes transmembrane proteins of the golgi body, which play an important role in the transport of protein in cells. It is reported that CS can be caused by disorders of glycosylation, which is considered to be the result of the variants of VPS13B [4-6]. Pendred syndrome (PDS; OMIM#274600) was firstly described as a combination of deafness and goiter by V.Pendred in 1896. SLC26A4 gene is located on chromosome 7q31, encodes a type of anion transporter called Pendrin, which was cloned in 1997[7]. The variants of SLC26A4 can result in PDS, enlarged vestibular aqueduct (EVA) and inherited deafness. Typical clinical phenotypes of PDS include goiter, congenital sensorineural deafness and an abnormal organification of iodide[8-10]. Few cases of VPS13B gene variation have been reported in China, and homozygous variants are much less. This is the first case of homozygous VPS13B variation combined with homozygous SLC26A4 variation. Case Presentation A 65-day-old girl was admitted to Tianjin Children’s Hospital for hearing loss, poor feeding and slow growth. This infant was born after 38+1 weeks of gestation uncomplicated pregnancy by normal spontaneous vaginal delivery, weight 3200 g. There were no abnormalities in placenta and umbilical cord during pregnancy except premature rupture of membranes 20 h in advance. The condition of newborn was normal without history of fetal intrauterine distress and postnatal asphyxia. She Cried immediately and loudly after birth, the apgar score was 10 at 1 min. Physical examination after admission showed that the head circumference, body length and body weight were 36 cm, 53 cm and 3840 g respectively. Moreover, she presented wih bilateral eye strabismus, hypertonia (both upper limbs), hypotonia (both lower limbs) and unsound original reflex. No swelling and nodule were touched in bilateral thyroid gland. Blood routine examination showed that white blood cells were 13070/μL and the neutral ratio was 13%. Thyroid function test showed that the total thyroid hormone was 160.62 nmol/L (78.38-157.4 nmol/L), and the free thyroid hormone was 20.19 pmol/L (9.92-19.54 nmol/L). No specific abnormal fatty acid metabolism was found in the blood and urine screening of genetic metabolic diseases. Other blood and urine stool results were generally normal. Cranial MRI showed that the ventricles and the extra brain space were widened. Brainstem auditory evoked potential showed moderate to severe hearing loss in the right ear and severe hearing loss in left ear. The results of deafness gene screening showed homozygous c.919-2A>G variation of SLC26A4 gene. Then hereditary deafness was diagnosed. After a period of targeted treatment, the symptoms of the patient did not improve significantly. The possibility of other genetic diseases was considered after consultation with the rehabilitation department, ophthalmology department and neurology department. The chromosome test showed 46, XX, whole-exome sequencing (WES) showed the co-occurrence of homozygous c.6940+1G>T variation of VPS13B gene and homozygous c.919-2A>G variation of SLC26A4 gene. Sanger sequencing showed that the parents of the patient were heterozygous carriers of both pathogenic genes ( Figure 1 and Figure 2 ). The patient cannot be diagnosed with PDS due to the lack of parents' permission about some special examinations. CS and hereditary deafness were diagnosed according to hearing test and other tests. At 1.5 years of telephone follow-up, the patient showed apparently growth retardation (height 76 cm, weight 6000 g). She presented with normal head circumference, a long and thin face, and two eyes (cross-eye) with normal vision. Her hearing was normal in her mother’s opinion, because she could move her sight with her mother's voice and respond to small sound stimulation in life. No swelling and nodule were touched in bilateral thyroid gland. She could hold up her head, sit up and roll without the help of an adult, and could stand with the help of her parents. There is considerable muscular hypotonia and psychomotor retardation. She could only speak simple words such as BABA and MAMA. (The above was her mother's dictation.) Discussion And Conclusions We introduced a 65-day-old female infant with co-occurrence of homozygous variants of two pathogenic genes. In this case, the splicing-site variation c.6940+1G>T of VPS13B gene has been reported in some Chinese patients and its clinical significance on Clinvar was described as likely pathogenic. Because of the clinical heterogeneity and the clinical manifestations vary in different regions, the correlation between genotype and phenotype has not been determined[11]. The clinical manifestations of CS in Finnish patients are highly uniform, and there is phenotypic variability in non-Finnish patients. The common clinical manifestations are psychomotor retardation, microcephaly, characteristic facial features, progressive retinochoroidal dystrophy, hypotonia and neutropenia[12]. With the number of patients gradually increases, more cases with rare clinical manifestations are also increasing, including pulmonary hypertension, congenital defects of the genital organ, insulin resistance, diabetes, febrile convulsion, epilepsy and other clinical manifestations[13, 14]. We reviewed the medical records on the patient, including the growth, development and related examination results. We found that the clinical manifestations of this case were atypical, including hypotonia, dyspnea, poor feeding, poor weight gain, binocular strabismus, neutropenia and other clinical features. The infant was born with premature rupture of membranes 20h in advance and postnatal evaluation was normal, there was no report describing the relationship between premature rupture of membranes and CS. Other manifestations were inconsistent with the typical patients described in previous articles[13, 15, 16]. Only some mothers had oligohydramnios and decreased fetal movement during pregnancy, so we can't determine whether premature rupture of membranes is associated with CS[13]. The birth weight of patient was not significantly abnormal compared with normal newborns. The weight of patient won’t increase because of the poor feeding caused by muscular hypotonia, so infant patients often show poor weight gain rather than typical facial features[17]. Just one case of bilateral strabismus in CS was reported in China[18], However, due to the absence of fundus examination and obvious clinical heterogeneity among patients with CS, it is impossible to determine whether there is damage to photoreceptor cilia and integrity of retinal structure[19]. So we can’t judge whether strabismus is one of the manifestation of CS. In 2016, CS was first diagnosed by WES in China[20]. Here, we reviewed all the patients with CS confirmed by gene examinations in China ( Table 1 ) and analyzed the gene variant sites and clinical features. It was found that 5 of 12 patients (including current case) carried c.6940+1G>T variant of VPS13B gene[20-22]. Only this patient was homozygous, and the other 4 cases were heterozygous variation. It can be found that Chinese patients with CS have a high c.6940+1G>T variant carrying rate, which may be a hotspot variation in Chinese population. The variant frequency of this site is 0.01997% in all population ant that is 0.1% in East Asian population. It is obvious that the variant frequency of East Asian population is higher than other populations, and there is little reports about this variation in other populations[23-28]. The c.6940+1G>T variation was first discovered by Chinese doctor in 2016, and has been reported four times in China in recent years[20-22]. This patient is the fifth case but the first homozygous variation patient in China. Due to the early symptoms are atypical and the diagnosis is difficult, only this child is under 1 year of age, which proves the value of WES in early diagnose. Therefore, it is necessary to detect VPS13B gene when newborns exhibit microcephaly, hypotonia, neutropenia and developmental retardation[17]. SLC26A4 gene variation is one of the main causes of neonatal deafness in China, which can cause both syndromic deafness and non-syndromic deafness[29, 30]. The prevalence of PDS is about 10-7.5/100000, accounting for 10% of congenital deafness cases[9, 31]. The variation of SLC26A4 gene in this patient was c.919-2A>G (intron7), which was described as pathogenic on Clinvar. It can be manifested as PDS, EVA and hereditary deafness. As goiter mostly occurs in children and adolescents, it is easy to be affected by external iodine intake, resulting in atypical goiter in some children[9]. The patient in this study did not appear thyroid abnormalities. The parents refused the examination of CT and MRI, so we don’t know whether there are abnormalities in the vestibular aqueduct and cochlea. Typical PDS patients can find inner ear malformation, EVA and Mondini cochlea[9]. The diagnosis of PDS mainly depends on the typical clinical manifestations, perchlorate excretion test, imaging findings of cochlear dysplasia and enlarged vestibular aqueduct. Therefore, the patient could not be diagnosed with PDS and was temporarily diagnosed with hereditary deafness at discharge. We found the hearing was normal at 1.5-year telephone follow up. There are two cases of double allelic deafness gene variation (both included c.919-2A>G) were reported to have normal hearing, so the possibility of false positive brainstem auditory evoked potentials was not excluded[32, 33]. It was reported that 32.7% of newborns with abnormal hearing screening were fully recovered and 9.7% were partially recovered, but the outcomes of newborns with genetic abnormalities wasn’t mentioned[34]. It has been reported that non syndromic EVA is caused by 0 or 1 SLC26A4 allele variation, while PDS is caused by two allele variants[35]. Therefore, it is a highly reliable indication of PDS. Because the early symptoms are atypical, it is difficult to make an early diagnosis among infants with CS[36]. With the popularity of WES, the accuracy of clinical diagnosis has been greatly improved. We should consider the possibility of genetic diseases if we find that some clinical manifestations can’t be explained. The patient's deafness gene screening showed SLC26A4 variation, it can provide an explanation for the hearing loss of infants, but some symptoms couldn’t be explained after admission. Hence WES was performed and homozygous SLC26A4 gene variation combined with homozygous VPS13B gene variation were found, which explained other symptoms. Many diseases of the newborn are atypical, especially in some genetic diseases, that further increases the difficulty of diagnosis by neonatal pediatricians. Obviously, WES is worthwhile for early diagnosis of difficult neonatal cases and it is helpful for genetic counseling[36-39]. In recent years, the value of copy number variation analysis based on WES in phenotypic diversity of related genetic diseases has been reported[40]. Early diagnosis and early intervention are helpful to improve the prognosis of patients, and the treatment mainly relying on multidisciplinary cooperation in symptomatic support treatment. For example, insulin resistance in CS can be avoided by early nutrition education and diet control[41], early thyroid hormone replacement therapy can avoid goiter in patients with PDS, and hearing aids or cochlear implants can significantly improve the quality of life of people with hearing loss[42]. In this study, we describe a patient with co-occurrence of homozygous variants SLC26A4 and VPS13B gene. The high frequency of c.6940+1G>T in Chinese population with CS indicates that may be a hotspot variation, and it is helpful to clarify the pathogenicity of this site. It is difficult to make early diagnosis due to the atypical symptoms. WES can effectively help clinical neonatologist make an early diagnosis. The early diagnosis and treatment can significantly improve the quality of life and prognosis of patients. Therefore WES has important diagnostic value in neonatal miscellaneous cases. Abbreviations CS: Cohen syndrome PDS: Pendred syndrome EVA: enlarged vestibular aqueduct WES: whole-exome sequencing DD: Developmental Delay MC: Microcephaly TFG: Typical Facial Gestalt TO: Trunk Obesity OS: Overly Sociable Behavior JH: Joint Hypermobility HM: High Myopia RD: Retinal Dystrophy IN: Intermittent Neutropenia Declarations Ethics approval and consent to participate This study involving human participants were reviewed and approved by the ethics committee of Tianjin Children's hospital. Written informed consent was obtained from minor’s legal guardian for publication of this case report and any accompanying images or data included in this article. Consent for publication Written informed consent was obtained from the patient/parents/legal guardians for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding The study was supported by the National Natural Science Foundation of China [grant number 81771589]; the Program of Tianjin Science and Technology Plan (18ZXDBSY00170); the Tianjin Health Bureau Science and Technology (2014KZ031); Key project of Tianjin Children's Hospital (Y2020003). The funders designed this study and made data interpretation in the writing of this manuscript. Authors Contributions Yang Liu and Jianbo Shu designed this study and made data interpretation. Guoxu Li prepared the manuscript. Yu Mu and Chao Sun presented the clinical information of the patient and performed literature review. Jie Zheng, Xiaowei Xu, Xiaodan Yan and Fang Zhang performed the bioinformatics analyses. All authors provided their feedbacks on final manuscript. Acknowledgments We sincerely thank the patient and her parents for providing all of the clinical and laboratory information and samples. References Norio R, Raitta C, Lindahl E. Further delineation of the Cohen syndrome; report on chorioretinal dystrophy, leukopenia and consanguinity. Clin Genet. 1984;25(1):1-14. https://doi.org/10.1111/j.1399-0004.1984.tb00456.x. Cohen MM, Hall BD, Smith DW, Graham CB, Lampert KJ. A new syndrome with hypotonia, obesity, mental deficiency, and facial, oral, ocular, and limb anomalies. J Pediatr. 1973;83(2):280-284. https://doi.org/10.1016/s0022-3476(73)80493-7. 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Tables TABLE 1 : 12 patients with CS confirmed by gene examinations in China References Sex Age Variations DD MC TFG TO OSB JH HM and/or RD IN Yin L et al.[20] male 2 years c.5086C>T c.6940＋1G>T + + - - + +- - + Zhang F et al.[43] male 1 year c.8868-1G>A c.11624-11625del + + + - + + - + Zhao S et al.[18] male 8 years c.3666+1G>T + + + - + + + + female 5 years c.9844A>T + + + - + + - - Yang C et al.[21] male 2 years c.5086C>T c.6940+1G>T + + +- - + + - + male 5 years c.3203C>T c.8016+7G>C + - - - - - - - male 3 years c.2199C>A c.553T>C + + +- - + +- - - male 3 years c.6940+1G>T c.9852-9855del + + +- - + +- - - Liao X et al.[44] male 4 years c.9259-1G＞C c.11104-11105de1 + + - - + + - + male 1 year c.9259-1G＞C c.11104-11105de1 + + - - + - - + Zhou J et al.[22] male 1 year c.6940+1G>T c.8531delG + + +- - + +- - + This case female 65 days c.6940+1G>T c.919-2A>G + - +- - - +- - + +: Typical symptom, +-: Atypical symptom, -: No symptom DD: Developmental Delay MC: Microcephaly TFG: Typical Facial Gestalt TO: Trunk Obesity OS: Overly Sociable Behavior JH: Joint Hypermobility HM: High Myopia RD: Retinal Dystrophy IN: Intermittent Neutropenia Supplementary Files CAREchecklistEnglish2013.docx 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. 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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-93977","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case report","associatedPublications":[],"authors":[{"id":3663876,"identity":"053e0f72-a344-4ba6-aa50-77f74cfd791e","order_by":0,"name":"Guoxu Li","email":"","orcid":"","institution":"Tianjin Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Guoxu","middleName":"","lastName":"Li","suffix":""},{"id":3663877,"identity":"534da03c-e5d1-406e-b3f9-44ec74033d79","order_by":1,"name":"Yu Mu","email":"","orcid":"","institution":"Tianjin Children's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Mu","suffix":""},{"id":3663878,"identity":"22f30b85-872c-4ca1-857e-a2a98cacf07a","order_by":2,"name":"Chao Sun","email":"","orcid":"","institution":"Tianjin Children's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chao","middleName":"","lastName":"Sun","suffix":""},{"id":3663879,"identity":"f6d39f98-11a7-44b9-b932-4fd1a0385c53","order_by":3,"name":"Jie Zheng","email":"","orcid":"","institution":"Tianjin Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Zheng","suffix":""},{"id":3663880,"identity":"adfc970d-4b6c-4424-b683-d72f2a49f42a","order_by":4,"name":"Xiaowei Xu","email":"","orcid":"","institution":"Tianjin Children's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaowei","middleName":"","lastName":"Xu","suffix":""},{"id":3663881,"identity":"cfc813dd-615c-464f-bc24-3b5391adf713","order_by":5,"name":"Xiaodan Yan","email":"","orcid":"","institution":"Tianjin Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaodan","middleName":"","lastName":"Yan","suffix":""},{"id":3663882,"identity":"e30a3b82-4acd-412d-b181-982fef1bcba0","order_by":6,"name":"Fang Zhang","email":"","orcid":"","institution":"Tianjin Children's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fang","middleName":"","lastName":"Zhang","suffix":""},{"id":3663883,"identity":"d81cd7e1-4844-43ea-b206-6b360b45d85b","order_by":7,"name":"Jianbo Shu","email":"","orcid":"","institution":"Tianjin Children's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jianbo","middleName":"","lastName":"Shu","suffix":""},{"id":3663884,"identity":"3f7e9d6a-671f-43ac-bb75-b471a63c7f57","order_by":8,"name":"Yang Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIiWNgGAWjYFCCAyDCgoGfmfnwA6I08DAcYGxgYJBgkGxnSzMgUgsDRIvBeR4FCaK02DMePv6Yt00icfNhHgYDhhqbaCJsOZbYDNKy7TDvgQcMx9JyGwhrOWMI1cKXYMDYcJgYLec/grVsbuYxkCBSyxlGsJYNzERrOXDMcOaccxLGMw4DAzmBGL+wzzj84MObMhvZ/v7DQFaNDWEtDBIHGJh42RgcwSoTCCoHAf4GBsYffxjsiVI8CkbBKBgFIxMAABcCQae9QBD+AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-3018-9671","institution":"Tianjin Children's Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2020-10-16 21:09:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-93977/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-93977/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":3118902,"identity":"92c92e92-9e47-40db-8f38-5a72ec17f419","added_by":"auto","created_at":"2020-10-21 22:01:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":16202,"visible":true,"origin":"","legend":"Pedigree: VPS13B and SLC26A4 variations in a Chinese family. The newborn was multiple genetic homozygous variants of SLC26A4 and VPS13B, the parents were heterozygous carriers of both pathogenic genes.","description":"","filename":"OnlineFIGURE1.Png","url":"https://assets-eu.researchsquare.com/files/rs-93977/v1/4e568a97916103de181b583e.Png"},{"id":3118903,"identity":"461d2cc8-d117-4244-9418-1e5634f23e9d","added_by":"auto","created_at":"2020-10-21 22:01:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":256385,"visible":true,"origin":"","legend":"Chromatograms of VPS13B and SLC26A4 variations. Sanger sequencing showed that the patient was homozygous c.6940+1G\u003eT variation of VPS13B gene and homozygous c.919-2A\u003eG variation of SLC26A4 gene, the parents of the patient were heterozygous carriers of both pathogenic genes.","description":"","filename":"OnlineFIGURE2.Png","url":"https://assets-eu.researchsquare.com/files/rs-93977/v1/a2c90a08478e89ca6a60cd1a.Png"},{"id":13604788,"identity":"2c772497-d789-4848-8171-8b348ac8af85","added_by":"auto","created_at":"2021-09-17 06:01:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":606049,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-93977/v1/a713d6a0-213b-4feb-85f8-59f1cf7dfb76.pdf"},{"id":3118904,"identity":"02c1300b-15be-4838-b11e-6e13b0ad7afe","added_by":"auto","created_at":"2020-10-21 22:01:04","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":34621,"visible":true,"origin":"","legend":"","description":"","filename":"CAREchecklistEnglish2013.docx","url":"https://assets-eu.researchsquare.com/files/rs-93977/v1/c3252dc269fc89f96924d17b.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eCo-existence of Cohen Syndrome and Pendred Syndrome? Diagnostic Challenges Associated With Presence of Multiple Genomic Variants in the Newborn: A Case Report\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eCohen syndrome (CS; OMIM#216550) was first described in 1968 with the name of the patient\u0026rsquo;s name for Pepper syndrome[1]. Then it was confirmed by Cohen and the colleagues in 1973 and named as CS[2]. CS is an autosomal recessive genetic multisystem disease. The clinical manifestations of different ethnic groups have been proved to be different, the classical manifestations include characteristic facial features, microcephaly, trunk obesity, mental retardation, progressive retinopathy and intermittent congenital neutropenia, etc[1, 2]. \u003cem\u003eVPS13B \u003c/em\u003egene was cloned in 2004, the germline variation of \u003cem\u003eVPS13B\u003c/em\u003e gene on chromosome 8q22.2 is considered to be the hereditary cause of CS[3]. \u003cem\u003eVPS13B\u003c/em\u003e contains 66 exons, spans a genomic region of approximately 864 kb[3, 4]. It mainly encodes transmembrane proteins of the golgi body, which play an important role in the transport of protein in cells. It is reported that CS can be caused by disorders of glycosylation, which is considered to be the result of the variants of \u003cem\u003eVPS13B\u003c/em\u003e[4-6].\u003c/p\u003e\n\u003cp\u003ePendred syndrome (PDS; OMIM#274600) was firstly described as a combination of deafness and goiter by V.Pendred in 1896. \u003cem\u003eSLC26A4\u003c/em\u003e gene is located on chromosome 7q31, encodes a type of anion transporter called Pendrin, which was cloned in 1997[7]. The variants of \u003cem\u003eSLC26A4\u003c/em\u003e can result in PDS, enlarged vestibular aqueduct (EVA) and inherited deafness. Typical clinical phenotypes of PDS include goiter, congenital sensorineural deafness and an abnormal organification of iodide[8-10]. Few cases of \u003cem\u003eVPS13B\u003c/em\u003e gene variation have been reported in China, and homozygous variants are much less. This is the first case of homozygous \u003cem\u003eVPS13B\u003c/em\u003e variation combined with homozygous \u003cem\u003eSLC26A4\u003c/em\u003e variation.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 65-day-old girl was admitted to Tianjin Children\u0026rsquo;s Hospital for hearing loss, poor feeding and slow growth. This infant was born after 38+1 weeks of gestation uncomplicated pregnancy by normal spontaneous vaginal delivery, weight 3200 g. There were no abnormalities in placenta and umbilical cord during pregnancy except premature rupture of membranes 20 h in advance. The condition of newborn was normal without history of fetal intrauterine distress and postnatal asphyxia. She Cried immediately and loudly after birth, the apgar score was 10 at 1 min. Physical examination after admission showed that the head circumference, body length and body weight were 36 cm, 53 cm and 3840 g respectively. Moreover, she presented wih bilateral eye strabismus, hypertonia (both upper limbs), hypotonia (both lower limbs) and unsound original reflex. No swelling and nodule were touched in bilateral thyroid gland. Blood routine examination showed that white blood cells were 13070/\u0026mu;L and the neutral ratio was 13%. Thyroid function test showed that the total thyroid hormone was 160.62 nmol/L (78.38-157.4 nmol/L), and the free thyroid hormone was 20.19 pmol/L (9.92-19.54 nmol/L). No specific abnormal fatty acid metabolism was found in the blood and urine screening of genetic metabolic diseases. Other blood and urine stool results were generally normal. Cranial MRI showed that the ventricles and the extra brain space were widened. Brainstem auditory evoked potential showed moderate to severe hearing loss in the right ear and severe hearing loss in left ear. The results of deafness gene screening showed homozygous c.919-2A\u0026gt;G variation of \u003cem\u003eSLC26A4\u003c/em\u003e gene. Then hereditary deafness was diagnosed. After a period of targeted treatment, the symptoms of the patient did not improve significantly. The possibility of other genetic diseases was considered after consultation with the rehabilitation department, ophthalmology department and neurology department. The chromosome test showed 46, XX, whole-exome sequencing (WES) showed the co-occurrence of homozygous c.6940+1G\u0026gt;T variation of \u003cem\u003eVPS13B\u003c/em\u003e gene and homozygous c.919-2A\u0026gt;G variation of \u003cem\u003eSLC26A4\u003c/em\u003e gene. Sanger sequencing showed that the parents of the patient were heterozygous carriers of both pathogenic genes (\u003cstrong\u003eFigure 1 and Figure 2\u003c/strong\u003e). The patient cannot be diagnosed with PDS due to the lack of parents' permission about some special examinations. CS and hereditary deafness were diagnosed according to hearing test and other tests.\u003c/p\u003e\n\u003cp\u003eAt 1.5 years of telephone follow-up, the patient showed apparently growth retardation (height 76 cm, weight 6000 g). She presented with normal head circumference, a long and thin face, and two eyes (cross-eye) with normal vision. Her hearing was normal in her mother\u0026rsquo;s opinion, because she could move her sight with her mother's voice and respond to small sound stimulation in life. No swelling and nodule were touched in bilateral thyroid gland. She could hold up her head, sit up and roll without the help of an adult, and could stand with the help of her parents. There is considerable muscular hypotonia and psychomotor retardation. She could only speak simple words such as BABA and MAMA. (The above was her mother's dictation.)\u003c/p\u003e"},{"header":"Discussion And Conclusions","content":"\u003cp\u003eWe introduced a 65-day-old female infant with co-occurrence of homozygous variants of two pathogenic genes. In this case, the splicing-site variation c.6940+1G\u0026gt;T of \u003cem\u003eVPS13B\u003c/em\u003e gene has been reported in some Chinese patients and its clinical significance on Clinvar was described as likely pathogenic. Because of the clinical heterogeneity and the clinical manifestations vary in different regions, the correlation between genotype and phenotype has not been determined[11]. The clinical manifestations of CS in Finnish patients are highly uniform, and there is phenotypic variability in non-Finnish patients. The common clinical manifestations are psychomotor retardation, microcephaly, characteristic facial features, progressive retinochoroidal dystrophy, hypotonia and neutropenia[12]. With the number of patients gradually increases, more cases with rare clinical manifestations are also increasing, including pulmonary hypertension, congenital defects of the genital organ, insulin resistance, diabetes, febrile convulsion, epilepsy and other clinical manifestations[13, 14]. We reviewed the medical records on the patient, including the growth, development and related examination results. We found that the clinical manifestations of this case were atypical, including hypotonia, dyspnea, poor feeding, poor weight gain, binocular strabismus, neutropenia and other clinical features. The infant was born with premature rupture of membranes 20h in advance and postnatal evaluation was normal, there was no report describing the relationship between premature rupture of membranes and CS. Other manifestations were inconsistent with the typical patients described in previous articles[13, 15, 16]. Only some mothers had oligohydramnios and decreased fetal movement during pregnancy, so we can't determine whether premature rupture of membranes is associated with CS[13]. The birth weight of patient was not significantly abnormal compared with normal newborns. The weight of patient won\u0026rsquo;t increase because of the poor feeding caused by muscular hypotonia, so infant patients often show poor weight gain rather than typical facial features[17]. Just one case of bilateral strabismus in CS was reported in China[18], However, due to the absence of fundus examination and obvious clinical heterogeneity among patients with CS, it is impossible to determine whether there is damage to photoreceptor cilia and integrity of retinal structure[19]. So we can\u0026rsquo;t judge whether strabismus is one of the manifestation of CS.\u003c/p\u003e\n\u003cp\u003eIn 2016, CS was first diagnosed by WES in China[20]. Here, we reviewed all the patients with CS confirmed by gene examinations in China (\u003cstrong\u003eTable 1\u003c/strong\u003e) and analyzed the gene variant sites and clinical features. It was found that 5 of 12 patients (including current case) carried c.6940+1G\u0026gt;T variant of \u003cem\u003eVPS13B\u003c/em\u003e gene[20-22]. Only this patient was homozygous, and the other 4 cases were heterozygous variation. It can be found that Chinese patients with CS have a high c.6940+1G\u0026gt;T variant carrying rate, which may be a hotspot variation in Chinese population. The variant frequency of this site is 0.01997% in all population ant that is 0.1% in East Asian population. It is obvious that the variant frequency of East Asian population is higher than other populations, and there is little reports about this variation in other populations[23-28]. The c.6940+1G\u0026gt;T variation was first discovered by Chinese doctor in 2016, and has been reported four times in China in recent years[20-22]. This patient is the fifth case but the first homozygous variation patient in China. Due to the early symptoms are atypical and the diagnosis is difficult, only this child is under 1 year of age, which proves the value of WES in early diagnose. Therefore, it is necessary to detect \u003cem\u003eVPS13B\u003c/em\u003e gene when newborns exhibit microcephaly, hypotonia, neutropenia and developmental retardation[17].\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSLC26A4\u003c/em\u003e gene variation is one of the main causes of neonatal deafness in China, which can cause both syndromic deafness and non-syndromic deafness[29, 30]. The prevalence of PDS is about 10-7.5/100000, accounting for 10% of congenital deafness cases[9, 31]. The variation of \u003cem\u003eSLC26A4\u003c/em\u003e gene in this patient was c.919-2A\u0026gt;G (intron7), which was described as pathogenic on Clinvar. It can be manifested as PDS, EVA and hereditary deafness. As goiter mostly occurs in children and adolescents, it is easy to be affected by external iodine intake, resulting in atypical goiter in some children[9]. The patient in this study did not appear thyroid abnormalities. The parents refused the examination of CT and MRI, so we don\u0026rsquo;t know whether there are abnormalities in the vestibular aqueduct and cochlea. Typical PDS patients can find inner ear malformation, EVA and Mondini cochlea[9]. The diagnosis of PDS mainly depends on the typical clinical manifestations, perchlorate excretion test, imaging findings of cochlear dysplasia and enlarged vestibular aqueduct. Therefore, the patient could not be diagnosed with PDS and was temporarily diagnosed with hereditary deafness at discharge. We found the hearing was normal at 1.5-year telephone follow up. There are two cases of double allelic deafness gene variation (both included c.919-2A\u0026gt;G) were reported to have normal hearing, so the possibility of false positive brainstem auditory evoked potentials was not excluded[32, 33]. It was reported that 32.7% of newborns with abnormal hearing screening were fully recovered and 9.7% were partially recovered, but the outcomes of newborns with genetic abnormalities wasn\u0026rsquo;t mentioned[34]. It has been reported that non syndromic EVA is caused by 0 or 1 \u003cem\u003eSLC26A4\u003c/em\u003e allele variation, while PDS is caused by two allele variants[35]. Therefore, it is a highly reliable indication of PDS.\u003c/p\u003e\n\u003cp\u003eBecause the early symptoms are atypical, it is difficult to make an early diagnosis among infants with CS[36]. With the popularity of WES, the accuracy of clinical diagnosis has been greatly improved. We should consider the possibility of genetic diseases if we find that some clinical manifestations can\u0026rsquo;t be explained. The patient's deafness gene screening showed \u003cem\u003eSLC26A4\u003c/em\u003e variation, it can provide an explanation for the hearing loss of infants, but some symptoms couldn\u0026rsquo;t be explained after admission. Hence WES was performed and homozygous \u003cem\u003eSLC26A4\u003c/em\u003e gene variation combined with homozygous \u003cem\u003eVPS13B\u003c/em\u003e gene variation were found, which explained other symptoms. Many diseases of the newborn are atypical, especially in some genetic diseases, that further increases the difficulty of diagnosis by neonatal pediatricians. Obviously, WES is worthwhile for early diagnosis of difficult neonatal cases and it is helpful for genetic counseling[36-39]. In recent years, the value of copy number variation analysis based on WES in phenotypic diversity of related genetic diseases has been reported[40].\u003c/p\u003e\n\u003cp\u003eEarly diagnosis and early intervention are helpful to improve the prognosis of patients, and the treatment mainly relying on multidisciplinary cooperation in symptomatic support treatment. For example, insulin resistance in CS can be avoided by early nutrition education and diet control[41], early thyroid hormone replacement therapy can avoid goiter in patients with PDS, and hearing aids or cochlear implants can significantly improve the quality of life of people with hearing loss[42].\u003c/p\u003e\n\u003cp\u003eIn this study, we describe a patient with co-occurrence of homozygous variants \u003cem\u003eSLC26A4\u003c/em\u003e and \u003cem\u003eVPS13B\u003c/em\u003e gene. The high frequency of c.6940+1G\u0026gt;T in Chinese population with CS indicates that may be a hotspot variation, and it is helpful to clarify the pathogenicity of this site. It is difficult to make early diagnosis due to the atypical symptoms. WES can effectively help clinical neonatologist make an early diagnosis. The early diagnosis and treatment can significantly improve the quality of life and prognosis of patients. Therefore WES has important diagnostic value in neonatal miscellaneous cases.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCS: Cohen syndrome\u003c/p\u003e\n\u003cp\u003ePDS: Pendred syndrome\u003c/p\u003e\n\u003cp\u003eEVA: enlarged vestibular aqueduct\u003c/p\u003e\n\u003cp\u003eWES: whole-exome sequencing\u003c/p\u003e\n\u003cp\u003eDD: Developmental Delay\u003c/p\u003e\n\u003cp\u003eMC: Microcephaly\u003c/p\u003e\n\u003cp\u003eTFG: Typical Facial Gestalt\u003c/p\u003e\n\u003cp\u003eTO: Trunk Obesity\u003c/p\u003e\n\u003cp\u003eOS: Overly Sociable Behavior\u003c/p\u003e\n\u003cp\u003eJH: Joint Hypermobility\u003c/p\u003e\n\u003cp\u003eHM: High Myopia\u003c/p\u003e\n\u003cp\u003eRD: Retinal Dystrophy\u003c/p\u003e\n\u003cp\u003eIN: Intermittent Neutropenia\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study involving human participants were reviewed and approved by the ethics committee of Tianjin Children's hospital. Written informed consent was obtained from minor\u0026rsquo;s legal guardian for publication of this case report and any accompanying images or data included in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient/parents/legal guardians for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was supported by the National Natural Science Foundation of China [grant number 81771589]; the Program of Tianjin Science and Technology Plan (18ZXDBSY00170); the Tianjin Health Bureau Science and Technology (2014KZ031); Key project of Tianjin Children's Hospital (Y2020003). The funders designed this study and made data interpretation in the writing of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYang Liu and Jianbo Shu designed this study and made data interpretation. Guoxu Li prepared the manuscript. Yu Mu and Chao Sun presented the clinical information of the patient and performed literature review. Jie Zheng, Xiaowei Xu, Xiaodan Yan and Fang Zhang performed the bioinformatics analyses. All authors provided their feedbacks on final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe sincerely thank the patient and her parents for providing all of the clinical and laboratory information and samples.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eNorio R, Raitta C, Lindahl E. Further delineation of the Cohen syndrome; report on chorioretinal dystrophy, leukopenia and consanguinity. Clin Genet. 1984;25(1):1-14. https://doi.org/10.1111/j.1399-0004.1984.tb00456.x.\u003c/li\u003e\n\u003cli\u003eCohen MM, Hall BD, Smith DW, Graham CB, Lampert KJ. A new syndrome with hypotonia, obesity, mental deficiency, and facial, oral, ocular, and limb anomalies. J Pediatr. 1973;83(2):280-284. https://doi.org/10.1016/s0022-3476(73)80493-7.\u003c/li\u003e\n\u003cli\u003eVelayos-Baeza A, Vettori A, Copley RR, Dobson-Stone C, Monaco AP. Analysis of the human VPS13 gene family. Genomics. 2004;84(3):536-549. https://doi.org/10.1016/j.ygeno.2004.04.012.\u003c/li\u003e\n\u003cli\u003eKolehmainen J, Black GC, Saarinen A, et al. Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am J Hum Genet. 2003;72(6):1359-1369. https://doi.org/10.1086/375454.\u003c/li\u003e\n\u003cli\u003eSeifert W, K\u0026uuml;hnisch J, Maritzen T, Horn D, Haucke V, Hennies HC. Cohen syndrome-associated protein, COH1, is a novel, giant Golgi matrix protein required for Golgi integrity. J Biol Chem. 2011;286(43):37665-37675. https://doi.org/10.1074/jbc.M111.267971.\u003c/li\u003e\n\u003cli\u003eDuplomb L, Duvet S, Picot D, et al. Cohen syndrome is associated with major glycosylation defects. Hum Mol Genet. 2014;23(9):2391-2399. https://doi.org/10.1093/hmg/ddt630.\u003c/li\u003e\n\u003cli\u003eEverett LA, Glaser B, Beck JC, et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet. 1997;17(4):411-422. https://doi.org/10.1038/ng1297-411.\u003c/li\u003e\n\u003cli\u003eBizhanova A, Kopp P. Genetics and phenomics of Pendred syndrome. Mol Cell Endocrinol. 2010;322(1-2):83-90. https://doi.org/10.1016/j.mce.2010.03.006.\u003c/li\u003e\n\u003cli\u003eW\u0026eacute;meau JL, Kopp P. Pendred syndrome. Best Pract Res Clin Endocrinol Metab. 2017;31(2):213-224. https://doi.org/10.1016/j.beem.2017.04.011.\u003c/li\u003e\n\u003cli\u003eAlper SL, Sharma AK. The SLC26 gene family of anion transporters and channels. Mol Aspects Med. 2013;34(2-3):494-515. https://doi.org/10.1016/j.mam.2012.07.009.\u003c/li\u003e\n\u003cli\u003eDouzgou S, Petersen MB. Clinical variability of genetic isolates of Cohen syndrome. Clin Genet. 2011;79(6):501-506. https://doi.org/10.1111/j.1399-0004.2011.01669.x.\u003c/li\u003e\n\u003cli\u003eNorio R. Finnish Disease Heritage I: characteristics, causes, background. Hum Genet. 2003;112(5-6):441-456. https://doi.org/10.1007/s00439-002-0875-3.\u003c/li\u003e\n\u003cli\u003eChandler KE, Kidd A, Al-Gazali L, et al. Diagnostic criteria, clinical characteristics, and natural history of Cohen syndrome. J Med Genet. 2003;40(4):233-241. https://doi.org/10.1136/jmg.40.4.233.\u003c/li\u003e\n\u003cli\u003eCokkinos P, Gkouziouta A, Karavolias G, Kariofillis P, Voudris V. Idiopathic pulmonary arterial hypertension in a young patient with the Cohen syndrome. Hellenic J Cardiol. 2013;54(2):143-146.\u003c/li\u003e\n\u003cli\u003eKivitie-Kallio S, Norio R. Cohen syndrome: essential features, natural history, and heterogeneity. Am J Med Genet. 2001;102(2):125-135. https://doi.org/10.1002/1096-8628(20010801)102:2\u0026lt;125::aid-ajmg1439\u0026gt;3.0.co;2-0.\u003c/li\u003e\n\u003cli\u003eEl Chehadeh-Djebbar S, Blair E, Holder-Espinasse M, et al. Changing facial phenotype in Cohen syndrome: towards clues for an earlier diagnosis. Eur J Hum Genet. 2013;21(7):736-742. https://doi.org/10.1038/ejhg.2012.251.\u003c/li\u003e\n\u003cli\u003eRodrigues JM, Fernandes HD, Caruthers C, Braddock SR, Knutsen AP. Cohen Syndrome: Review of the Literature. Cureus. 2018;10(9):e3330. https://doi.org/10.7759/cureus.3330.\u003c/li\u003e\n\u003cli\u003eZhao S, Luo Z, Xiao Z, et al. Case report: two novel VPS13B mutations in a Chinese family with Cohen syndrome and hyperlinear palms. BMC Med Genet. 2019;20(1):187. https://doi.org/10.1186/s12881-019-0920-x.\u003c/li\u003e\n\u003cli\u003eUyhazi KE, Binenbaum G, Carducci N, Zackai EH, Aleman TS. Early photoreceptor outer segment loss and retinoschisis in Cohen syndrome. Ophthalmic Genet. 2018;39(3):399-404. https://doi.org/10.1080/13816810.2018.1459735.\u003c/li\u003e\n\u003cli\u003eYin L, Cheng M, Wang Y, et al. Case report of Cohen syndrome and literature review. Chin J Appl Clin Pediatr. 2016;31(19):1498-1499. https://doi.org/10.3760/cma.j.issn.2095-428X.2016.19.016 (In Chinese).\u003c/li\u003e\n\u003cli\u003eYang C, Hou M, Li Y, et al. Gene analysis: A rare gene disease of intellectual deficiency-Cohen syndrome. Int J Dev Neurosci. 2018;68:83-88. https://doi.org/10.1016/j.ijdevneu.2018.05.004.\u003c/li\u003e\n\u003cli\u003eZhou J, Huang H, Wen F, Li L, Zhu Q, Wang H. Severe congenital neutropenia: a report of 2 cases and literature review. J Clin Pediatr. 2020;38(1):61-64. https://doi.org/10.3969/j.issn.1000-3606.2020.01.015 (In Chinese).\u003c/li\u003e\n\u003cli\u003eSeifert W, Holder-Espinasse M, K\u0026uuml;hnisch J, et al. Expanded mutational spectrum in Cohen syndrome, tissue expression, and transcript variants of COH1. Hum Mutat. 2009;30(2):E404-420. https://doi.org/10.1002/humu.20886.\u003c/li\u003e\n\u003cli\u003eAlipour N, Salehpour S, Tonekaboni SH, et al. Mutations in the VPS13B Gene in Iranian Patients with Different Phenotypes of Cohen Syndrome. J Mol Neurosci. 2020;70(1):21-25. https://doi.org/10.1007/s12031-019-01394-w.\u003c/li\u003e\n\u003cli\u003eRejeb I, Jilani H, Elaribi Y, et al. First case report of Cohen syndrome in the Tunisian population caused by VPS13B mutations. BMC Med Genet. 2017;18(1):134. https://doi.org/10.1186/s12881-017-0493-5.\u003c/li\u003e\n\u003cli\u003eFalk MJ, Feiler HS, Neilson DE, et al. Cohen syndrome in the Ohio Amish. Am J Med Genet A. 2004;128A(1):23-28. https://doi.org/10.1002/ajmg.a.30033.\u003c/li\u003e\n\u003cli\u003eBugiani M, Gyftodimou Y, Tsimpouka P, et al. Cohen syndrome resulting from a novel large intragenic COH1 deletion segregating in an isolated Greek island population. Am J Med Genet A. 2008;146A(17):2221-2226. https://doi.org/10.1002/ajmg.a.32239.\u003c/li\u003e\n\u003cli\u003eKolehmainen J, Wilkinson R, Lehesjoki AE, et al. Delineation of Cohen syndrome following a large-scale genotype-phenotype screen. Am J Hum Genet. 2004;75(1):122-127. https://doi.org/10.1086/422197.\u003c/li\u003e\n\u003cli\u003eDai P, Huang LH, Wang GJ, et al. Concurrent Hearing and Genetic Screening of 180,469 Neonates with Follow-up in Beijing, China. Am J Hum Genet. 2019;105(4):803-812. https://doi.org/10.1016/j.ajhg.2019.09.003.\u003c/li\u003e\n\u003cli\u003eFang Y, Gu M, Wang C, Suo F, Wang G, Xia Y. GJB2 as Well as SLC26A4 Gene Mutations are Prominent Causes for Congenital Deafness. Cell Biochem Biophys. 2015;73(1):41-44. https://doi.org/10.1007/s12013-015-0562-3.\u003c/li\u003e\n\u003cli\u003eKoffler T, Ushakov K, Avraham KB. Genetics of Hearing Loss: Syndromic. Otolaryngol Clin North Am. 2015;48(6):1041-1061. https://doi.org/10.1016/j.otc.2015.07.007.\u003c/li\u003e\n\u003cli\u003eZhao X, Huang L, Wang X, et al. Genotyping and audiological characteristics of infants with a single-allele SLC26A4 mutation. Int J Pediatr Otorhinolaryngol. 2019;116:153-158. https://doi.org/10.1016/j.ijporl.2018.10.046.\u003c/li\u003e\n\u003cli\u003eSuppiej A, Rizzardi E, Zanardo V, Franzoi M, Ermani M, Orzan E. Reliability of hearing screening in high-risk neonates: comparative study of otoacoustic emission, automated and conventional auditory brainstem response. Clin Neurophysiol. 2007;118(4):869-876. https://doi.org/10.1016/j.clinph.2006.12.015.\u003c/li\u003e\n\u003cli\u003ePsarommatis I, Voudouris C, Kapetanakis I, Athanasiadi F, Douros K. Recovery of Abnormal ABR in Neonates and Infants at Risk of Hearing Loss. Int J Otolaryngol. 2017;2017:7912127. https://doi.org/10.1155/2017/7912127.\u003c/li\u003e\n\u003cli\u003ePryor SP, Madeo AC, Reynolds JC, et al. SLC26A4/PDS genotype-phenotype correlation in hearing loss with enlargement of the vestibular aqueduct (EVA): evidence that Pendred syndrome and non-syndromic EVA are distinct clinical and genetic entities. J Med Genet. 2005;42(2):159-165. https://doi.org/10.1136/jmg.2004.024208.\u003c/li\u003e\n\u003cli\u003eAbu Diab A, AlTalbishi A, Rosin B, et al. The combination of whole-exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies. Acta Ophthalmol. 2019;97(6):e877-877e886. https://doi.org/10.1111/aos.14095.\u003c/li\u003e\n\u003cli\u003eKelsen JR, Dawany N, Moran CJ, et al. Exome sequencing analysis reveals variants in primary immunodeficiency genes in patients with very early onset inflammatory bowel disease. Gastroenterology. 2015;149(6):1415-1424. https://doi.org/10.1053/j.gastro.2015.07.006.\u003c/li\u003e\n\u003cli\u003eBodian DL, Kothiyal P, Hauser NS. Pitfalls of clinical exome and gene panel testing: alternative transcripts. Genet Med. 2019;21(5):1240-1245. https://doi.org/10.1038/s41436-018-0319-7.\u003c/li\u003e\n\u003cli\u003eSheppard S, Biswas S, Li MH, et al. Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss. Genet Med. 2018;20(12):1663-1676. https://doi.org/10.1038/s41436-018-0004-x.\u003c/li\u003e\n\u003cli\u003eEnomoto Y, Tsurusaki Y, Yokoi T, et al. CNV analysis using whole exome sequencing identified biallelic CNVs of VPS13B in siblings with intellectual disability. Eur J Med Genet. 2020;63(1):103610. https://doi.org/10.1016/j.ejmg.2018.12.015.\u003c/li\u003e\n\u003cli\u003eLimoge F, Faivre L, Gautier T, et al. Insulin response dysregulation explains abnormal fat storage and increased risk of diabetes mellitus type 2 in Cohen Syndrome. Hum Mol Genet. 2015;24(23):6603-6613. https://doi.org/10.1093/hmg/ddv366.\u003c/li\u003e\n\u003cli\u003eRoesch S, Moser G, Rasp G, T\u0026oacute;th M. CT-scans of cochlear implant patients with characteristics of Pendred syndrome. Cell Physiol Biochem. 2013;32(7):166-172. https://doi.org/10.1159/000356636.\u003c/li\u003e\n\u003cli\u003eZhang F, Shi XY, Liu LY, Liu YT, Zou LP. [Psychomotor retardation with neutropenia for more than one year in a toddler]. Zhongguo Dang Dai Er Ke Za Zhi. 2018;20(6):497-500.\u003c/li\u003e\n\u003cli\u003eLiao X, Qiu K, Qin L, Zhou X, He Z. Cohen syndrome:two cases report and literature review. Chin J Obstet Gynecol Pediatr ( Electron Ed ). 2020;16(1):59-66. https://doi.org/10.3877/cma.j.issn.1673-5250.2020.01.008 (In Chinese).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTABLE 1\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e 12 patients with CS confirmed by gene examinations in China\u003c/p\u003e\n\u003ctable border=\"1\" width=\"576\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"89\"\u003e\n\u003cp\u003eReferences\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eSex\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eAge\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003eVariations\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003eDD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"33\"\u003e\n\u003cp\u003eMC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"37\"\u003e\n\u003cp\u003eTFG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30\"\u003e\n\u003cp\u003eTO\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003eOSB\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28\"\u003e\n\u003cp\u003eJH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"72\"\u003e\n\u003cp\u003eHM and/or RD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"27\"\u003e\n\u003cp\u003eIN\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"89\"\u003e\n\u003cp\u003eYin L et al.[20]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003emale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003e2 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003ec.5086C\u0026gt;T\u003c/p\u003e\n\u003cp\u003ec.6940＋1G\u0026gt;T\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"33\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"37\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28\"\u003e\n\u003cp\u003e+-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"72\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"27\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"89\"\u003e\n\u003cp\u003eZhang F et al.[43]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003emale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003e1 year\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003ec.8868-1G\u0026gt;A\u003c/p\u003e\n\u003cp\u003ec.11624-11625del\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"33\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"37\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"72\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"27\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"89\"\u003e\n\u003cp\u003eZhao S et al.[18]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003emale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003e8 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003ec.3666+1G\u0026gt;T\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"33\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"37\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"72\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"27\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"89\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003efemale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003e5 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003ec.9844A\u0026gt;T\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"33\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"37\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"72\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"27\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"89\"\u003e\n\u003cp\u003eYang C et al.[21]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003emale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003e2 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003ec.5086C\u0026gt;T\u003c/p\u003e\n\u003cp\u003ec.6940+1G\u0026gt;T\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"33\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"37\"\u003e\n\u003cp\u003e+-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"72\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"27\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"89\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003emale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003e5 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003ec.3203C\u0026gt;T\u003c/p\u003e\n\u003cp\u003ec.8016+7G\u0026gt;C\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"33\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"37\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"72\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"27\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"89\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003emale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003e3 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003ec.2199C\u0026gt;A\u003c/p\u003e\n\u003cp\u003ec.553T\u0026gt;C\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"33\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"37\"\u003e\n\u003cp\u003e+-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28\"\u003e\n\u003cp\u003e+-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"72\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"27\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"89\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003emale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003e3 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003ec.6940+1G\u0026gt;T\u003c/p\u003e\n\u003cp\u003ec.9852-9855del\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"33\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"37\"\u003e\n\u003cp\u003e+-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28\"\u003e\n\u003cp\u003e+-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"72\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"27\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"89\"\u003e\n\u003cp\u003eLiao X et al.[44]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003emale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003e4 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003ec.9259-1G＞C\u003c/p\u003e\n\u003cp\u003ec.11104-11105de1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"33\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"37\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"72\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"27\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"89\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003emale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003e1 year\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003ec.9259-1G＞C\u003c/p\u003e\n\u003cp\u003ec.11104-11105de1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"33\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"37\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"72\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"27\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"89\"\u003e\n\u003cp\u003eZhou J et al.[22]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003emale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003e1 year\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003ec.6940+1G\u0026gt;T\u003c/p\u003e\n\u003cp\u003ec.8531delG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"33\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"37\"\u003e\n\u003cp\u003e+-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28\"\u003e\n\u003cp\u003e+-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"72\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"27\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"89\"\u003e\n\u003cp\u003eThis case\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003efemale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003e65 days\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003ec.6940+1G\u0026gt;T\u003c/p\u003e\n\u003cp\u003ec.919-2A\u0026gt;G\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"33\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"37\"\u003e\n\u003cp\u003e+-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28\"\u003e\n\u003cp\u003e+-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"72\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"27\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e+: Typical symptom, +-: Atypical symptom, -: No symptom\u003c/p\u003e\n\u003cp\u003eDD: Developmental Delay\u003c/p\u003e\n\u003cp\u003eMC: Microcephaly\u003c/p\u003e\n\u003cp\u003eTFG: Typical Facial Gestalt\u003c/p\u003e\n\u003cp\u003eTO: Trunk Obesity\u003c/p\u003e\n\u003cp\u003eOS: Overly Sociable Behavior\u003c/p\u003e\n\u003cp\u003eJH: Joint Hypermobility\u003c/p\u003e\n\u003cp\u003eHM: High Myopia\u003c/p\u003e\n\u003cp\u003eRD: Retinal Dystrophy\u003c/p\u003e\n\u003cp\u003eIN: Intermittent Neutropenia\u003c/p\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":"Cohen syndrome, VPS13B gene, Pendred syndrome, SLC26A4 gene, Genetic deafness","lastPublishedDoi":"10.21203/rs.3.rs-93977/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-93977/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\u003cp\u003eCohen syndrome is a multisystem autosomal recessive hereditary disease, which is caused by variants of the \u003cem\u003eVPS13B\u003c/em\u003e gene. The clinical manifestations include characteristic facial features, microcephaly, trunk obesity and mental retardation. The \u003cem\u003eSLC26A4\u003c/em\u003e gene encodes an anion transporter called Pendrin, the variants of \u003cem\u003eSLC26A4\u003c/em\u003e lead to deafness, Pendred syndrome and enlarged vestibular aqueduct. We presence a case of multiple genetic homozygous variants of \u003cem\u003eSLC26A4\u003c/em\u003e and \u003cem\u003eVPS13B.\u003c/em\u003e\u003c/p\u003e\u003cp\u003eCase presentation\u003c/p\u003e\u003cp\u003eIn this study, we described a case of a 65-day-old female infant presenting with hearing loss and poor feeding. The deafness gene screening before admission showed that the patient carried homozygous c.919-2A\u0026gt;G\u0026nbsp;variation of\u003cem\u003e SLC26A4 \u003c/em\u003egene. The symptoms of the patient did not improve significantly after a period of targeted treatment, then the possibility of genetic diseases was considered after consultation with the different departments. Whole exome sequencing was performed, and homozygous splicing variants in intron 38 (c.6940+1G\u0026gt;T) of \u003cem\u003eVPS13B \u003c/em\u003eand that in intron 7 (c.919-2A\u0026gt;G) of \u003cem\u003eSLC26A4\u003c/em\u003e were identified. Later, the parent was proved as the carriers of \u003cem\u003eVPS13B\u003c/em\u003e and \u003cem\u003eSLC26A4\u003c/em\u003e heterozygous\u0026nbsp;variations by Sanger sequencing.\u003c/p\u003e\u003cp\u003eConclusions\u003c/p\u003e\u003cp\u003ePresence of multiple genetic homozygous variants of \u003cem\u003eSLC26A4\u003c/em\u003e and \u003cem\u003eVPS13B\u003c/em\u003e, it is difficult to make an early diagnosis due to early atypical symptoms. Final diagnosis depends on whole exome sequencing which plays an important role in early diagnosis of intractable neonatal cases.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Co-existence of Cohen Syndrome and Pendred Syndrome? Diagnostic Challenges Associated With Presence of Multiple Genomic Variants in the Newborn: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-10-21 22:01:02","doi":"10.21203/rs.3.rs-93977/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":"eccb80f6-a687-446d-a6f3-11c44beb99f2","owner":[],"postedDate":"October 21st, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":844964,"name":"Pediatrics"}],"tags":[],"updatedAt":"2021-02-17T11:25:08+00:00","versionOfRecord":[],"versionCreatedAt":"2020-10-21 22:01:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-93977","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-93977","identity":"rs-93977","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}