Prelingual Sensorineural Hearing Loss Caused by a Novel <i>GJB2</i> Dominant Mutation in a Chinese Family

Huang, Shasha; Gao, Xue; Wang, Yufeng; Kang, Dongyang; Zhang, Xin; Yang, Su-Yan; Dai, Pu

doi:10.1155/2020/6370386

Cited by 4 publications

(4 citation statements)

References 14 publications

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“…For example, c.205T>C (p.F69L) was reported in trans with c.35delG in a proband with hearing loss (PM3), implying an autosomal recessive manner. Huang et al reported that this variant co-segregated with prelingual nonsyndromic sensorineural hearing loss in a dominant pattern, supporting the activation of PP1_Moderate 31. As a result, we applied PM3, PM2, PP3 for c.205T>C for autosomal recessive, and PP1_Moderate, PM2, PP3 for autosomal dominant.…”

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confidence: 68%

Comprehensive simulation and interpretation of single nucleotide substitutions in GJB2 reveals the genetic and phenotypic landscape of GJB2-related hearing loss

Xiang

Song

et al. 2021

Preprint

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Genetic variants in the GJB2 gene are the most frequent causes of congenital and childhood hearing loss worldwide. In addition to nonsyndromic hearing loss, GJB2 pathogenic variants are also correlated with syndromic phenotypes, showing high genetic and phenotypic heterogeneity. To comprehensively delineate the genetic and phenotypic landscape of GJB2 variants, we interpreted and manually curated all the 2043 possible single-nucleotide substitution (SNS) coding variants in this gene following the hearing loss-specific ACMG/AMP guidelines. As a result, 61 (3.0%), 188 (9.2%), 1487 (72.8%), 301 (14.7%) and 6 (0.3%) variants were classified as pathogenic, likely pathogenic, variant of uncertain significance, likely benign and benign, respectively. Interestingly, 54% (84/156) of pathogenic/likely pathogenic missense variants were not recorded in ClinVar. Further analysis showed that the second transmembrane domain (TM2) and the 310 helix are highly enriched for pathogenic missense variants. The N-terminal tail and the extracellular loop (E1) showed a high density of variants that are associated with syndromic or dominant nonsyndromic hearing loss. On the other hand, the intracellular loops (CL and CT) were extremely tolerant to variation. Based on this new information, we propose refinements of the guidelines for variant interpretation in GJB2. In summary, our study interpreted all possible SNS variants in the coding region of the GJB2 gene, characterized novel clinically significant (N = 249) and benign or likely benign (N = 307) in this gene, and revealed significant genotype-phenotype correlations at this common hearing loss locus. The interpretation of GJB2 SNS variants in the coding region provides a prototype for genes with similarly high genetic and phenotypic heterogeneity.

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confidence: 68%

Comprehensive simulation and interpretation of single nucleotide substitutions in GJB2 reveals the genetic and phenotypic landscape of GJB2-related hearing loss

Xiang

Song

et al. 2021

Preprint

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“…Since 2003, our team has been working on the molecular etiologies and precaution of hereditary HL, and up to now, 22,456 cases have been tested for the identification of molecular etiologies. Various advancements have been made in the study on the pathogenic factors in the Chinese HL population ( Dai et al, 2009a ; Dai et al, 2009b ; Dai et al, 2019 ; Yuan et al, 2020 ), resulting in the identification of new genes ( Yuan et al, 2014 ; Gao et al, 2018a ; Zhao et al, 2019 ) or novel variants ( Gao et al, 2018b ; Gao et al, 2020 ; Huang et al, 2020 ). We could identify the molecular etiology through gene sequencing in 52.19% of patients with HL ( Yuan et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Gene4HL: An Integrated Genetic Database for Hearing Loss

Huang

Zhao

et al. 2021

Front. Genet.

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Hearing loss (HL) is one of the most common disabilities in the world. In industrialized countries, HL occurs in 1–2/1,000 newborns, and approximately 60% of HL is caused by genetic factors. Next generation sequencing (NGS) has been widely used to identify many candidate genes and variants in patients with HL, but the data are scattered in multitudinous studies. It is a challenge for scientists, clinicians, and biologists to easily obtain and analyze HL genes and variant data from these studies. Thus, we developed a one-stop database of HL-related genes and variants, Gene4HL (http://www.genemed.tech/gene4hl/), making it easy to catalog, search, browse and analyze the genetic data. Gene4HL integrates the detailed genetic and clinical data of 326 HL-related genes from 1,608 published studies, along with 62 popular genetic data sources to provide comprehensive knowledge of candidate genes and variants associated with HL. Additionally, Gene4HL supports the users to analyze their own genetic engineering network data, performs comprehensive annotation, and prioritizes candidate genes and variations using custom parameters. Thus, Gene4HL can help users explain the function of HL genes and the clinical significance of variants by correlating the genotypes and phenotypes in humans.

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“…The severity of hearing loss was classified into 5 grades: normal <26 Decibel (dB); mild = 26–40 dB; moderate = 41–70 dB; severe = 71–90 dB and profound >90 dB, as suggested previously. 26 The blood pressure (BP) was measured by an electronic sphygmomanometer and repeated for 3 times. Hypertension was defined according to the guidelines of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC VI), as a systolic BP≥140 mmHg or the diastolic BP≥90 mmHg.…”

Section: Methodsmentioning

confidence: 99%

Mutational Analysis of Mitochondrial tRNA Genes in 200 Patients with Type 2 Diabetes Mellitus

Lin¹,

Zhang²,

Jin³

et al. 2021

IJGM

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Objective: Previous studies showed that variants in mitochondrial DNA (mtDNA) are associated with type 2 diabetes mellitus (T2DM). However, the relationships between mitochondrial tRNA (mt-tRNA) variants and T2DM remain poorly understood. Methods: In this study, we performed a mutational screening of 22 mt-tRNA genes in a cohort of 200 Han Chinese subjects with T2DM and 200 control subjects through PCR-Sanger sequencing. The identified mt-tRNA variants were assessed for their pathogenicity via the phylogenetic approach, structural and functional analysis. Furthermore, two Han Chinese pedigrees with maternally inherited diabetes and deafness (MIDD) were reported by clinical and genetic assessments. Results: A total of 49 genetic variants in mt-tRNA genes were identified; among them, 31 variants (17 pathogenic/likely pathogenic) were absent in controls, located at extremely conserved nucleotides, may have potential structural and functional significance, thereby considered to be T2DM-associated variants. In addition, sequence analysis of entire mitochondrial genomes of the matrilineal relatives from two MIDD pedigrees revealed the occurrence of tRNA Leu(UUR) A3243G and T3290C mutations, as well as sets of polymorphisms belonging to mitochondrial haplogroups F2 and D4. However, the lack of any functional variants in connexin 26 gene (GJB2) and tRNA 5-methylaminomethyl-2-thiouridylate (TRMU) suggested that nuclear genes may not play active roles in clinical expression of MIDD in these pedigrees. Conclusion: Our data indicated that mt-tRNA variants were associated with T2DM, screening for mt-tRNA pathogenic mutations was recommended for early detection and prevention of mitochondrial diabetes.

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Prelingual Sensorineural Hearing Loss Caused by a Novel GJB2 Dominant Mutation in a Chinese Family

Cited by 4 publications

References 14 publications

Comprehensive simulation and interpretation of single nucleotide substitutions in GJB2 reveals the genetic and phenotypic landscape of GJB2-related hearing loss

Comprehensive simulation and interpretation of single nucleotide substitutions in GJB2 reveals the genetic and phenotypic landscape of GJB2-related hearing loss

Gene4HL: An Integrated Genetic Database for Hearing Loss

Mutational Analysis of Mitochondrial tRNA Genes in 200 Patients with Type 2 Diabetes Mellitus

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