Dataset Information

When transcripts matter: delineating between non-syndromic hearing loss DFNB32 and hearing impairment infertile male syndrome (HIIMS).

ABSTRACT: Mutations in the CDC14A (Cell Division-Cycle 14A) gene, which encodes a conserved dual-specificity protein tyrosine phosphatase, have been identified as a cause of autosomal recessive non-syndromic hearing loss (DFNB32) and hearing impairment infertility male syndrome (HIIMS). We used next-generation sequencing to screen six deaf probands from six families segregating sensorineural moderate-to-profound hearing loss. Data analysis and variant prioritization were completed using a custom bioinformatics pipeline. We identified three homozygous loss of function variants (p.Arg345Ter, p.Arg376Ter, and p.Ala451Thrfs*43) in the CDC14A gene, segregating with deafness in each family. Of the six families, four segregated the p.Arg376Ter mutation, one family segregated the p.Arg345Ter mutation and one family segregated a novel frameshift (p.Ala451Thrfs*43) mutation. In-depth phenotyping of affected individuals ruled out secondary syndromic findings. This study implicates the p.Arg376Ter mutation might be as a founder mutation in the Iranian population. It also provides the first semen analysis for deaf males carrying mutations in exon 11 of CDC14A and reveals a genotype-phenotype correlation that delineates between DFNB32 and HIIMS. The clinical results from affected males suggest the NM_033313.2 transcript alone is sufficient for proper male fertility, but not for proper auditory function. We conclude that DFNB32 is a distinct phenotypic entity in males.

SUBMITTER: Mohseni M

PROVIDER: S-EPMC7651993 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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When transcripts matter: delineating between non-syndromic hearing loss DFNB32 and hearing impairment infertile male syndrome (HIIMS).

Mohseni Marzieh M Akbari Mojdeh M Booth Kevin T KT Babanejad Mojgan M Azaiez Hela H Ardalani Fariba F Arzhangi Sanaz S Jalalvand Khadijeh K Nikzat Nooshin N Ghodratpour Fatemeh F Jamali Payman P Adeli Omid Ali OA Habibi Haleh H Kahrizi Kimia K Najmabadi Hossein H

Journal of human genetics 20200330 7

Mutations in the CDC14A (Cell Division-Cycle 14A) gene, which encodes a conserved dual-specificity protein tyrosine phosphatase, have been identified as a cause of autosomal recessive non-syndromic hearing loss (DFNB32) and hearing impairment infertility male syndrome (HIIMS). We used next-generation sequencing to screen six deaf probands from six families segregating sensorineural moderate-to-profound hearing loss. Data analysis and variant prioritization were completed using a custom bioinform ...[more]

PMID: 32231217

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Project description:BACKGROUND:Sensorineural 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. METHODS:We 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. RESULTS:The 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). CONCLUSIONS:In 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.

Dataset Information

When transcripts matter: delineating between non-syndromic hearing loss DFNB32 and hearing impairment infertile male syndrome (HIIMS).

Publications

When transcripts matter: delineating between non-syndromic hearing loss DFNB32 and hearing impairment infertile male syndrome (HIIMS).

Similar Datasets

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