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Elucidation of the unique mutation spectrum of severe hearing loss in a Vietnamese pediatric population.

ABSTRACT: The mutational spectrum of deafness in Indochina Peninsula, including Vietnam, remains mostly undetermined. This significantly hampers the progress toward establishing an effective genetic screening method and early customized rehabilitation modalities for hearing loss. In this study, we evaluated the genetic profile of severe-to-profound hearing loss in a Vietnamese pediatric population using a hierarchical genetic analysis protocol that screened 11 known deafness-causing variants, followed by massively parallel sequencing targeting 129 deafness-associated genes. Eighty-seven children with isolated severe-to-profound non-syndromic hearing loss without family history were included. The overall molecular diagnostic yield was estimated to be 31.7%. The mutational spectrum for severe-to-profound non-syndromic hearing loss in our Vietnamese population was unique: The most prevalent variants resided in the MYO15A gene (7.2%), followed by GJB2 (6.9%), MYO7A (5.5%), SLC26A4 (4.6%), TMC1 (1.8%), ESPN (1.8%), POU3F4 (1.8%), MYH14 (1.8%), EYA1 (1.8%), and MR-RNR1 (1.1%). The unique spectrum of causative genes in the Vietnamese deaf population was similar to that in the southern Chinese deaf population. It is our hope that the mutation spectrum provided here could aid in establishing an efficient protocol for genetic analysis of severe-to-profound hearing loss and a customized screening kit for the Vietnamese population.

SUBMITTER: Han JJ

PROVIDER: S-EPMC6367484 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Elucidation of the unique mutation spectrum of severe hearing loss in a Vietnamese pediatric population.

Han Jae Joon JJ Nguyen Pham Dinh PD Oh Doo-Yi DY Han Jin Hee JH Kim Ah-Reum AR Kim Min Young MY Park Hye-Rim HR Tran Lam Huyen LH Dung Nguyen Huu NH Koo Ja-Won JW Lee Jun Ho JH Oh Seung Ha SH Anh Vu Hoang H Choi Byung Yoon BY

Scientific reports 20190207 1

The mutational spectrum of deafness in Indochina Peninsula, including Vietnam, remains mostly undetermined. This significantly hampers the progress toward establishing an effective genetic screening method and early customized rehabilitation modalities for hearing loss. In this study, we evaluated the genetic profile of severe-to-profound hearing loss in a Vietnamese pediatric population using a hierarchical genetic analysis protocol that screened 11 known deafness-causing variants, followed by ...[more]

PMID: 30733538

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Project description:Mutations in Gap Junction Beta 2 (GJB2) have been reported to be a major cause of non-syndromic hearing loss in many populations worldwide. The spectrums and frequencies of GJB2 variants vary substantially among different ethnic groups, and the genotypes among these populations remain poorly understood. In the present study, we carried out a systematic and extended mutational screening of GJB2 gene in 1067 Han Chinese subjects with non-syndromic hearing loss, and the resultant GJB2 variants were evaluated by phylogenetic, structural and bioinformatic analysis. A total of 25 (23 known and 2 novel) GJB2 variants were identified, including 6 frameshift mutations, 1 nonsense mutation, 16 missense mutations and 2 silent mutations. In this cohort, c.235delC is the most frequently observed pathogenic mutation. The phylogenetic, structural and bioinformatic analysis showed that 2 novel variants c.127G>T (p.V43L), c.293G>C (p.R98P) and 2 known variants c. 107T>C (p.L36P) and c.187G>T (p.V63L) are localized at highly conserved amino acids. In addition, these 4 mutations are absent in 203 healthy individuals, therefore, they are probably the most likely candidate pathogenic mutations. In addition, 66 (24 novel and 42 known) genotypes were identified, including 6 homozygotes, 20 compound heterozygotes, 18 single heterozygotes, 21 genotypes harboring only polymorphism(s) and the wild type genotype. Among these, 153 (14.34%) subjects were homozygous for pathogenic mutations, 63 (5.91%) were compound heterozygotes, and 157 (14.71%) carried single heterozygous mutation. Furthermore, 65.28% (141/216) of these cases with two pathogenic mutations exhibited profound hearing loss. These data suggested that mutations in GJB2 gene are responsible for approximately 34.96% of non-syndromic hearing loss in Han Chinese population from Zhejiang Province in eastern China. In addition, our results also strongly supported the idea that other factors such as alterations in regulatory regions, additional genes, and environmental factors may contribute to the clinical manifestation of deafness.

Project description:BackgroundHearing loss (HL) is a heterogeneous condition that causes partial or complete hearing impairment. Hundreds of variants in >60 genes have been reported to be associated with Hereditary HL (HHL), variants of the GJB2 gene are the most common cause of congenital SNHL, with >100 variants reported. The HHL prevalence is thought to be high in the Arab population; however, the genetic epidemiology of HHL among Emirati populations is understudied.AimsTo shed light on the mutational spectrum of NSHL in Emirati patients seen in the genetic clinic over 10 years and to capture founder mutation(s) if any were identified.MethodsRetrospective chart review of all Emirati patients assessed by clinical geneticists due to NSHL during the period between January 2010 to December 2020. Genetic tests were done based on clinical phenotypes of the patient and family history including targeted mutation testing, next-generation sequencing, or whole-exome sequencing (solo or trio). The authors did literature reviews using PubMed for all previously reported articles related to NSHL genes from UAE.ResultsA total of 162 patients with HL, were evaluated during the period between January 2010 to December 2020. There were 82 patients with NSHL, and only 72 patients who completed the genetic evaluations were included in this retrospective study. Among the studied group, 42 (51.2%) were males and 40 (48.78%) were females. The youngest patient was 2 years old and the oldest patient was 50 years old. Consanguinity was documented in 76 patients (92.68%). A total of 14 mutations reported here are novel (23/72 i.e., 31.9%). Twelve missense mutations, 6 nonsense mutations, 6 frameshift mutations, 2 in-frame deletion mutations, and 1 splice site mutation was found. Variants in the GJB2 gene are the most commonly identified cause of NSHL, with c.35delG being the most followed by c.506G > A. The second commonly found variant is c.934C > G (p.Arg312Gly) in the CDC14A gene, found in 9 patients. This was followed by variants in OTOF and SLC26A4 genes, found in 8 patients, respectively. Chromosomal microdeletions encompassing genes causing NSHL were found in 3 patients. No mitochondrial mutations were found in this study group. A total of 11 previous reports about Emirati patients with NSHL were reviewed, with a total of 35 patients.ConclusionEmirati patients with NSHL have several mutations, most notably missense mutations. Novel mutations are worth further testing and represent the area for future researches.

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Elucidation of the unique mutation spectrum of severe hearing loss in a Vietnamese pediatric population.

Publications

Elucidation of the unique mutation spectrum of severe hearing loss in a Vietnamese pediatric population.

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