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Diagnostic outcomes of exome sequencing in patients with syndromic or non-syndromic hearing loss.

ABSTRACT: Hereditary hearing loss (HL) is a common sensory disorder, with an incidence of 1-2 per 1000 newborns, and has a genetic etiology in over 50% of cases. It occurs either as part of a syndrome or in isolation and is genetically very heterogeneous which poses a challenge for clinical and molecular diagnosis. We used exome sequencing to seek a genetic cause in a group of 56 subjects (49 probands) with HL: 32 with non-syndromic non-GJB2 HL and 17 with syndromic HL. Following clinical examination and clinical exome sequencing, an etiological diagnosis was established in 15 probands (15/49; 30%); eight (8/17;47%) from the syndromic group and seven (7/32; 21%) from the non-syndromic non-GJB2 subgroup. Fourteen different (half of them novel) non-GJB2 variants causing HL were found in 10 genes (CHD7, HDAC8, MITF, NEFL, OTOF, SF3B4, SLC26A4, TECTA, TMPRSS3, USH2A) among 13 probands, confirming the genetic heterogeneity of hereditary HL. Different genetic causes for HL were found in a single family while three probands with apparent syndromic HL were found to have HL as a separate clinical feature, distinct from the complex phenotype. Clinical exome sequencing proved to be an effective tool used to comprehensively address the genetic heterogeneity of HL, to detect clinically unrecognized HL syndromes, and to decipher complex phenotypes in which HL is a separate feature and not part of a syndrome.

SUBMITTER: Likar T

PROVIDER: S-EPMC5749682 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Diagnostic outcomes of exome sequencing in patients with syndromic or non-syndromic hearing loss.

Likar Tina T Hasanhodžić Mensuda M Teran Nataša N Maver Aleš A Peterlin Borut B Writzl Karin K

PloS one 20180102 1

Hereditary hearing loss (HL) is a common sensory disorder, with an incidence of 1-2 per 1000 newborns, and has a genetic etiology in over 50% of cases. It occurs either as part of a syndrome or in isolation and is genetically very heterogeneous which poses a challenge for clinical and molecular diagnosis. We used exome sequencing to seek a genetic cause in a group of 56 subjects (49 probands) with HL: 32 with non-syndromic non-GJB2 HL and 17 with syndromic HL. Following clinical examination and ...[more]

PMID: 29293505

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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.

Dataset Information

Diagnostic outcomes of exome sequencing in patients with syndromic or non-syndromic hearing loss.

Publications

Diagnostic outcomes of exome sequencing in patients with syndromic or non-syndromic hearing loss.

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