The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

Seco, Celia Zazo; Wesdorp, Mieke; Feenstra, Ilse; Pfundt, Rolph; Hehir-Kwa, Jayne Y.; Lelieveld, Stefan H.; Castelein, Steven; Gilissen, Christian; Wijs, Ilse J. de; Admiraal, R.J.C.; Pennings, Ronald J.E.; Kunst, Henricus P. M.; Kamp, Jiddeke M. van de; Tamminga, Saskia; Houweling, Arjan C.; Plomp, Astrid S.; Maas, Saskia M.; Gans, P. A. M. de Koning; Kant, Sarina G.; Geus, Christa M. de; Frints, Suzanna G.M.; Vanhoutte, Els K.; Dooren, Marieke F. van; Boogaard, Marie José H. Van Den; Scheffer, Hans; Nelen, Marcel; Kremer, Hannie; Hoefsloot, Lies H.; Schraders, Margit; Yntema, Helger G.

doi:10.1038/ejhg.2016.182

Cited by 98 publications

(69 citation statements)

References 40 publications

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“…Currently, the most cost-effective approach is using comprehensive panels of genes involved in inherited HI, which can provide sequencing data as well as detection of copy number variants (Shearer and Smith, 2015 ). Other laboratories use whole-exome sequencing followed by targeted analysis of genes known to be involved in HI (Zazo-Seco et al, 2017 ).…”

Section: Genetic Alterations That Results In Dfnb1 Hearing Impairmentmentioning

confidence: 99%

DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes

Castillo

2017

Front. Mol. Neurosci.

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The inner ear is a very complex sensory organ whose development and function depend on finely balanced interactions among diverse cell types. The many different kinds of inner ear supporting cells play the essential roles of providing physical and physiological support to sensory hair cells and of maintaining cochlear homeostasis. Appropriately enough, the gene most commonly mutated among subjects with hereditary hearing impairment (HI), GJB2, encodes the connexin-26 (Cx26) gap-junction channel protein that underlies both intercellular communication among supporting cells and homeostasis of the cochlear fluids, endolymph and perilymph. GJB2 lies at the DFNB1 locus on 13q12. The specific kind of HI associated with this locus is caused by recessively-inherited mutations that inactivate the two alleles of the GJB2 gene, either in homozygous or compound heterozygous states. We describe the many diverse classes of genetic alterations that result in DFNB1 HI, such as large deletions that either destroy the GJB2 gene or remove a regulatory element essential for GJB2 expression, point mutations that interfere with promoter function or splicing, and small insertions or deletions and nucleotide substitutions that target the GJB2 coding sequence. We focus on how these alterations disrupt GJB2 and Cx26 functions and on their different effects on cochlear development and physiology. We finally discuss the diversity of clinical features of DFNB1 HI as regards severity, age of onset, inner ear malformations and vestibular dysfunction, highlighting the areas where future research should be concentrated.

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Section: Genetic Alterations That Results In Dfnb1 Hearing Impairmentmentioning

confidence: 99%

DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes

Castillo

2017

Front. Mol. Neurosci.

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“…Therefore, MYO6 is considered an important causative gene for Japanese patients with ADSNHL. However, this is not a population-specific phenomenon as Seco et al recently also reported that the MYO6 gene is a frequent cause of AD hearing loss in the population in the Netherlands [30].…”

Section: Discussionmentioning

confidence: 91%

Clinical Characteristics and In Vitro Analysis of MYO6 Variants Causing Late-onset Progressive Hearing Loss

Oka

Day

Nishio

et al. 2020

Genes

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MYO6 is known as a genetic cause of autosomal dominant and autosomal recessive inherited hearing loss. In this study, to clarify the frequency and clinical characteristics of hearing loss caused by MYO6 gene mutations, a large-scale genetic analysis of Japanese patients with hearing loss was performed. By means of massively parallel DNA sequencing (MPS) using next-generation sequencing for 8074 Japanese families, we found 27 MYO6 variants in 33 families, 22 of which are novel. In total, 2.40% of autosomal dominant sensorineural hearing loss (ADSNHL) in families in this study (32 out of 1336) was found to be caused by MYO6 mutations. The present study clarified that most cases showed juvenile-onset progressive hearing loss and their hearing deteriorated markedly after 40 years of age. The estimated hearing deterioration was found to be 0.57 dB per year; when restricted to change after 40 years of age, the deterioration speed was accelerated to 1.07 dB per year. To obtain supportive evidence for pathogenicity, variants identified in the patients were introduced to MYO6 cDNA by site-directed mutagenesis and overexpressed in epithelial cells. They were then assessed for their effects on espin1-induced microvilli formation. Cells with wildtype myosin 6 and espin1 co-expressed created long microvilli, while co-expression with mutant constructs resulted in severely shortened microvilli. In conclusion, the present data clearly showed that MYO6 is one of the Genes 2020, 11, 273 2 of 14 genes to keep in mind with regard to ADSNHL, and the molecular characteristics of the identified gene variants suggest that a possible pathology seems to result from malformed stereocilia of the cochlear hair cells.

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“…Approximately 70% of affected individuals have nonsyndromic hearing loss (NSHL), which currently has over 115 recessive, dominant and/or X-linked genes implicated in its molecular pathogenesis (https :// hered itary heari ngloss.org/). The DFNB1 locus (GJB2 and GJB6) accounts for ~50% of severe to profound congenital NSHL cases, followed by USH2A, STRC, and MYO15A (Francey et al, 2012;Vona et al, 2015;Zazo Seco et al, 2016). Pathogenic recessive sequence variants in STRC were first reported in 2001 and this gene is now estimated to account for ~5%-6% of all congenital sensorineural hearing loss cases (Francey et al, 2012;Markova et al, 2018;Shearer et al, 2014;Sloan-Heggen et al, 2016;Vona et al, 2015); however, this could be an underestimate given the variable STRC allele frequencies between ethnicities (Sloan-Heggen et al, 2016) and the ongoing appreciation of clinically relevant copy number variation at the STRC locus.…”

Section: To the Editormentioning

confidence: 99%

Prenatal cytogenomic identification and molecular refinement of compound heterozygous STRC deletion breakpoints

Shi

Bai

Kharbutli

et al. 2019

Molec Gen & Gen Med

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Here, we report the prenatal detection of a compound heterozygous deletion at chromosome 15q15.3 by clinical chromosomal microarray (CMA) testing that included the CATSPER2 male infertility gene. However, given the low resolution of CMA at this homologous locus, it was unclear if the neighboring STRC hearing loss gene was also affected. Therefore, we developed a novel allele‐specific PCR strategy, which narrowed the proximal breakpoint of the maternally inherited deletion to a 310 bp interval that was 440 bp upstream from the STRC transcription start site.

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The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

Cited by 98 publications

References 40 publications

DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes

DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes

Clinical Characteristics and In Vitro Analysis of MYO6 Variants Causing Late-onset Progressive Hearing Loss

Prenatal cytogenomic identification and molecular refinement of compound heterozygous STRC deletion breakpoints

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