Dataset Information

SLC22A4 Gene in Hereditary Non-syndromic Hearing Loss: Recurrence and Incomplete Penetrance of the p.C113Y Mutation in Northwest Africa.

ABSTRACT: Inherited hearing loss is extremely heterogeneous both clinically and genetically. In addition, the spectrum of deafness-causing genetic variants differs greatly among geographical areas and ethnicities. The identification of the causal mutation in affected families allows early diagnosis, clinical follow-up, and genetic counseling. A large consanguineous family of Moroccan origin affected by autosomal recessive sensorineural hearing loss (ARSNHL) was subjected to genome-wide linkage analysis and exome sequencing. Exome-wide variant analysis and prioritization identified the SLC22A4 p.C113Y missense variant (rs768484124) as the most likely cause of ARSNHL in the family, falling within the unique significant (LOD score>3) linkage region on chromosome 5. Indeed, the same variant was previously reported in two Tunisian ARSNHL pedigrees. The variant is present in the homozygous state in all six affected individuals, but also in one normal-hearing sibling, suggesting incomplete penetrance. The mutation is absent in about 1,000 individuals from the Greater Middle East Variome study cohort, including individuals from the North African population, as well as in an additional seven deaf patients from the same geographical area, recruited and screened for mutations in the SLC22A4 gene. This study represents the first independent replication of the involvement of SLC22A4 in ARSNHL, highlighting the importance of the gene, and of the p.C113Y mutation, at least in the Northwest African population.

SUBMITTER: Chiereghin C

PROVIDER: S-EPMC7902881 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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<i>SLC22A4</i> Gene in Hereditary Non-syndromic Hearing Loss: Recurrence and Incomplete Penetrance of the p.C113Y Mutation in Northwest Africa.

Chiereghin Chiara C Robusto Michela M Mauri Lucia L Primignani Paola P Castorina Pierangela P Ambrosetti Umberto U Duga Stefano S Asselta Rosanna R Soldà Giulia G

Frontiers in genetics 20210210

Inherited hearing loss is extremely heterogeneous both clinically and genetically. In addition, the spectrum of deafness-causing genetic variants differs greatly among geographical areas and ethnicities. The identification of the causal mutation in affected families allows early diagnosis, clinical follow-up, and genetic counseling. A large consanguineous family of Moroccan origin affected by autosomal recessive sensorineural hearing loss (ARSNHL) was subjected to genome-wide linkage analysis an ...[more]

PMID: 33643381

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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.

Project description:Leber hereditary optic neuropathy (LHON) is a common cause of inherited blindness, primarily due to one of three mitochondrial DNA (mtDNA) mutations. These mtDNA pathogenic mutations have variable clinical penetrance. Recent linkage evidence raised the possibility that the nuclear gene optic atrophy 1 (OPA1) determines whether mtDNA mutation carriers develop blindness. To validate these findings we studied OPA1 in three independent LHON cohorts: sequencing the gene in discordant male sib pairs, carrying out a family-based association study of common functional genetic variants, and carrying out a population-based association study of the same genetic variants.We tested 3 hypothesis in three separate study groups. Study group 1: Direct sequencing of OPA1 coding regions was performed using sequencing methodologies (Applied Biosystems, Foster City, CA). Chromatograms were compared with the GenBank reference sequence NM_015560.1. Splice-site prediction was performed using GeneSplicer. Study group 2: Genotyping for rs166850 and rs10451941 was performed by restriction fragment length polymorphism (RFLP) analysis with specific primers for both genotypes, using The restriction enzymes RsaI and FspBI to discriminate genotypes. Study group 3: Genotyping for rs166850 and rs10451941 was performed by primer extension of allele-specific extensions products by matrix-associated laser desorption/ionisation time-of-flight (MALDI-TOF, Seqeunom, San Diego, CA) mass spectrometry. Allele and genotype frequencies were compared using Pearson's chi-square test. Multiple logistic regression was performed to look for interactions between the variables. All analyses were performed using SPSS software version 17.0 (SPSS Inc.).In all three groups we were unable to find an association between OPA1 genetic variation and visual failure in LHON mtDNA mutation carriers.Our findings suggest that genetic variation in OPA1 is unlikely to make a major contribution to the risk of blindness in LHON mutation carriers.

Dataset Information

SLC22A4 Gene in Hereditary Non-syndromic Hearing Loss: Recurrence and Incomplete Penetrance of the p.C113Y Mutation in Northwest Africa.

Publications

<i>SLC22A4</i> Gene in Hereditary Non-syndromic Hearing Loss: Recurrence and Incomplete Penetrance of the p.C113Y Mutation in Northwest Africa.

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