OTOGL复合杂合突变致常染色体隐性遗传非综合征型聋的遗传及听力表型分析
Analysis of Hearing Phenotype and Genetics of Autosomal Recessive Nonsyndromic Deafness Caused by Novel Compound Heterozygous Mutations in OTOGL
洪晗馨;王龙昊;刘辉辉;彭浒;林妘;许军;吴皓;杨涛
1:上海交通大学医学院附属第九人民医院耳鼻咽喉头颈外科
2:上海交通大学医学院耳科学研究所
3:上海市耳鼻疾病转化医学重点实验室
4:海军军医大学长征医院耳鼻咽喉科
摘要【Abstract】 Objective To study the etiology of a Chinese Han family with recessive non-syndromic hearing loss. Methods The clinical data of the family were collected, DNA was extracted after venous blood collection, and the full sequences of three common deafness genes (GJB2，SLC26A4，mitochondrial 12SrRNA) were screened by Sanger sequencing to exclude pathogenic mutations.Next-generation sequence of target capture was used to test all known deafness genes and look for the suspected causative deafness genes of the patient. Sanger sequencing was performed to verify the gene variants. Results The hearing phenotype of the proband was characterized by moderate hearing loss, and the bearing phenotype of his sister was characterized by moderate to severe hearing loss, but their parents had normal hearing. The screening of three major deafness gene of the proband did not reveal any likely pathogenic mutations. Through next-generation sequence of targeted capture and Sanger sequencing, it was found that the compound heterozygous mutation leading to truncated OTOGL gene was the highly likely genetic cause of the family. Both the proband and his sister carried the OTOGL gene c.2833C>T(p. Arg945 * )/c. 6467C>A(p.Ser2156 * ) compound heterozygous mutation that were inherited from their parents，respectively. According to the American College of medical genetics and genomics (ACMG) genetic variation classification standards and guidelines, both c. 2833C>T (p. Arg945 * ) and c. 6467C>A (p. Ser2156 * ) variants were identified. It is the first time that c. 2833C>T (p. Arg945 * ) was reported to be the pathogenic variant associated with hereditary deafness. Con- clusion The compound heterozygous variant of OTOGL gene c.2833C>T (p. Arg945 * ) and c. 6467C> A(p. Ser2156 * ) is highly likely to be the causative deafness gene in this family.
关键词基金项目(Foundation):作者参考文献1 Yariz KO,Duman D,Zazo SC,et al.Mutations in OTOGL,encoding the inner ear protein otogelin-like,cause moderate sensorineural hearing loss[J].Am J Hum Genet,2012,91(5):872-882.
2 Oonk AM,Leijendeckers JM,Huygen PL,et al.Similar phenotypes caused by mutations in OTOG and OTOGL[J].Ear Hear,2014,35(3):e84-91.
3 Richards S,Aziz N,Bale S,et al.Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J].Genet Med,2015,17(5):405-424.
4 Gu X,Sun S,Guo L,et al.Novel biallelic OTOGL mutations in a Chinese family with moderate non-syndromic sensorineural hearing loss[J].Int J Pediatr Otorhinolaryngol,2015,79(6):817-820.
5 Astuti GDN,Van DBLI,Khan MI,et al.Identification of inherited retinal disease-associated genetic variants in 11 candidate genes[J].Genes (Basel),2018,9(1):5-21.
6 Dror AA,Avraham KB.Hearing impairment:a panoply of genes and functions[J].Neuron,2010,68(2):293-308.
7 Verpy E,Leibovici M,Michalski N,et al.Stereocilin connects outer hair cell stereocilia to one another and to the tectorial membrane[J].J Comp Neurol,2011,519(2):194-210.
8 Francey LJ,Conlin LK,Kadesch HE,et al.Genome-wide SNP genotyping identifies the Stereocilin (STRC) gene as a major contributor to pediatric bilateral sensorineural hearing impairment[J].Am J Med Genet A,2012,158a(2):298-308.
9 Kim NK,Kim AR,Park KT,et al.Whole-exome sequencing reveals diverse modes of inheritance in sporadic mild to moderate sensorineural hearing loss in a pediatric population[J].Genet Med,2015,17(11):901-911.
10 Avan P,Le GS,Michel V,et al.Otogelin,otogelin-like,and stereocilin form links connecting outer hair cell stereocilia to each other and the tectorial membrane[J].Proc Natl Acad Sci USA,2019,116(51):25948-25957.
11 Bonnet C,Louha M,Loundon N,et al.Biallelic nonsense mutations in the otogelin-like gene (OTOGL) in a child affected by mild to moderate hearing impairment[J].Gene,2013,527(2):537-540.
12 Barake R,Abou RS,Nemer G,et al.The OTOGL p.Arg925* variant is associated with moderate hearing loss in a Syrian nonconsanguineous family[J].Genet Test Mol Biomarkers,2017,21(7):445-449.
13 Pavlenkova Z,Varga L,Borecka S,et al.Comprehensive molecular-genetic analysis of mid-frequency sensorineural hearing loss[J].Sci Rep,2021,11(1):22488.
14 任淑敏，孔祥东.一例中度听力损失的非综合征耳聋患儿的OTOGL基因变异分析[J].中华医学遗传学杂志，2021,38(8):761-764.
15 冯梦龙，黄莎莎，唐凤珠，等.OTOGL基因新变异致隐性遗传中度感音神经性耳聋的表型和基因型分析[J].中华医学杂志，2021,101(2):115-121.
16 Pan C,Li J,Wang S,et al.Novel heterozygous mutations in the otogelin-like (OTOGL) gene in a child with bilateral mild nonsyndromic sensorineural hearing loss[J].Gene,2022,808:146000.