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Genetic testing involving 100 common mutations for antenatal diagnosis of hereditary hearing loss in Chongqing, China.

ABSTRACT:

Abstract

To understand the possible carrier status of genes associated with hereditary hearing loss (HHL) in the general population among local residents and to give genetic counseling for pregnant women.A total of 3541 subjects were recruited. We used multiplex PCR technology combined with next-generation sequencing technology to detect 100 hotspot mutations in 18 common deafness-related genes. The homozygous mutation screening results were verified using Sanger sequencing.Of the 3541 participants, 37 alleles of 8 deafness genes were detected. A total of 145 (4.09%) were found to be GJB2 gene mutation carriers, and the hotspot mutation was c.235delC (1.54%). Twenty three (0.65%) were found to be GJB3 gene mutation carriers. A total of 132 (3.37%) were found to be SLC26A4 gene mutation carriers, and the hotspot mutation was c.919-2A > G (0.49%). Forty four (1.24%) were found to be mitochondrial DNA mutation carriers. Sanger sequencing results verified that 2 cases were homozygous for the c.235delC mutation and that 1 case was homozygous for the c.754T > C mutation.Genetic testing for pregnant women and their partners allows early identification of the molecular etiology of hearing loss (HL). On the one hand, it could give genetic counseling for pregnant women, such as early diagnosis of delayed deafness and drug-susceptible deafness. On the other hand, it could be used to assess hearing conditions during pregnancy, leading to prevention and timely intervention for newborns.

SUBMITTER: Hu H

PROVIDER: S-EPMC8084083 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSensorineural hearing loss (SNHL) is the most common sensory impairment. Comprehensive next-generation sequencing (NGS) has become the standard for the etiological diagnosis of early-onset SNHL. However, accurate selection of target genomic regions (gene panel/exome/genome), analytical performance and variant interpretation remain relevant difficulties for its clinical implementation.MethodsWe developed a novel NGS panel with 199 genes associated with non-syndromic and/or syndromic SNHL. We evaluated the analytical sensitivity and specificity of the panel on 1624 known single nucleotide variants (SNVs) and indels on a mixture of genomic DNA from 10 previously characterized lymphoblastoid cell lines, and analyzed 50 Spanish patients with presumed hereditary SNHL not caused by GJB2/GJB6, OTOF nor MT-RNR1 mutations.ResultsThe analytical sensitivity of the test to detect SNVs and indels on the DNA mixture from the cell lines was > 99.5%, with a specificity > 99.9%. The diagnostic yield on the SNHL patients was 42% (21/50): 47.6% (10/21) with autosomal recessive inheritance pattern (BSND, CDH23, MYO15A, STRC [n = 2], USH2A [n = 3], RDX, SLC26A4); 38.1% (8/21) autosomal dominant (ACTG1 [n = 3; 2 de novo], CHD7, GATA3 [de novo], MITF, P2RX2, SOX10), and 14.3% (3/21) X-linked (COL4A5 [de novo], POU3F4, PRPS1). 46.9% of causative variants (15/32) were not in the databases. 28.6% of genetically diagnosed cases (6/21) had previously undetected syndromes (Barakat, Usher type 2A [n = 3] and Waardenburg [n = 2]). 19% of genetic diagnoses (4/21) were attributable to large deletions/duplications (STRC deletion [n = 2]; partial CDH23 duplication; RDX exon 2 deletion).ConclusionsIn the era of precision medicine, obtaining an etiologic diagnosis of SNHL is imperative. Here, we contribute to show that, with the right methodology, NGS can be transferred to the clinical practice, boosting the yield of SNHL genetic diagnosis to 50-60% (including GJB2/GJB6 alterations), improving diagnostic/prognostic accuracy, refining genetic and reproductive counseling and revealing clinically relevant undiagnosed syndromes.

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Genetic testing involving 100 common mutations for antenatal diagnosis of hereditary hearing loss in Chongqing, China.

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