Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL

Abdelfatah, Nelly; McComiskey, David A.; Doucette, Lance P.; Griffin, Anne; Moore, Susan; Negrijn, Carol; Hodgkinson, Kathy; King, Justin J.; Larijani, Mani; Houston, Jim; Stanton, Susan G.; Young, Terry‐Lynn

doi:10.1038/ejhg.2013.5

Cited by 14 publications

(15 citation statements)

References 24 publications

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“…All probands recruited to the study were screened for population-specific deafness alleles (Supplementary Table 1; Abdelfatah et al 2013a, b; Ahmed et al 2004; Doucette et al 2009; Young et al 2001). To identify other candidate genes to screen, audiograms were submitted to Audiogene (Hildebrand et al 2009) for computerized comparison with known average audiograms of 16 autosomal dominant loci (under the assumption that hearing loss was segregating as an autosomal dominant trait in these NL families).…”

Section: Methodsmentioning

confidence: 99%

“…Microsatellites flanking candidate genes were genotyped according to standard procedures (Abdelfatah et al 2013a) and alleles called using GeneMapper software v4.0. Haplotypes were reconstructed manually and compared across families.…”

Section: Methodsmentioning

confidence: 99%

“…Religious and geographic isolation within small coastal fishing (outport) communities (Manion 1977) has resulted in a higher inbreeding coefficient in the NL population (Bear et al 1987, 1988; Zhai et al 2015). We have previously identified several founder deafness mutations in the NL populations (Abdelfatah et al 2013a, b; Ahmed et al 2004; Doucette et al 2009; Young et al 2001). …”

Section: Introductionmentioning

confidence: 99%

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A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect

et al. 2016

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Genetic isolates provide unprecedented opportunities to identify pathogenic mutations and explore the full natural history of clinically heterogeneous phenotypes such as hearing loss. We noticed a unique audioprofile, characterized by prelingual and rapid deterioration of hearing thresholds at frequencies >0.5 kHz in several adults from unrelated families from the island population of Newfoundland. Targeted serial Sanger sequencing of probands for deafness alleles (n = 23) that we previously identified in this founder population was negative. Whole exome sequencing in four members of the largest family (R2010) identified a CLDN14 (DFNB29) variant [c.488C>T; p. (Ala163Val)], likely pathogenic, sensorineural hearing loss, autosomal recessive. Although not associated with deafness or disease, CLDN14 p.(Ala163Val) has been previously reported as a variant of uncertain significance (VUS). Targeted sequencing of 169 deafness probands identified one homozygote and one heterozygous carrier. Genealogical studies, cascade sequencing and haplotype analysis across four unrelated families showed all subjects with the unique audioprofile (n = 12) were also homozygous for p.(Ala163Val) and shared a 1.4 Mb DFNB29-associated haplotype on chromosome 21. Most significantly, sequencing 175 population controls revealed 1% of the population are heterozygous for CLDN14 p.(Ala163Val), consistent with a major founder effect in Newfoundland. The youngest CLDN14 [c.488C>T; p.(Ala163Val)] homozygote passed newborn screening and had normal hearing thresholds up to 3 years of age, which then deteriorated to a precipitous loss >1 kHz during the first decade. Our study suggests that genetic testing may be necessary to identify at-risk children in time to prevent speech, language and developmental delay.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-016-1746-7) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect

et al. 2016

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“…The traditional method for ADNSHL diagnosis relies on the establishment of linkage to known DFNA loci in large pedigrees, followed by Sanger sequencing of candidate genes. This approach is not robust to phenotype misclassification, phenocopies caused by nongenetic causes, or the presence of locus heterogeneity within the same pedigree (e.g., Abdelfatah et al., ).…”

Section: Introductionmentioning

confidence: 99%

Exome Sequencing Identifies a Novel Frameshift Mutation ofMYO6as the Cause of Autosomal Dominant Nonsyndromic Hearing Loss in a Chinese Family

Cheng

Zhou

et al. 2014

Annals of Human Genetics

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SummaryAutosomal dominant types of nonsyndromic hearing loss (ADNSHL) are typically postlingual in onset and progressive. High genetic heterogeneity, late onset age, and possible confounding due to nongenetic factors hinder the timely molecular diagnoses for most patients. In this study, exome sequencing was applied to investigate a large Chinese family segregating ADNSHL in which we initially failed to find strong evidence of linkage to any locus by whole-genome linkage analysis. Two affected family members were selected for sequencing. We identified two novel mutations disrupting known ADNSHL genes and shared by the sequenced samples: c.328C>A in COCH (DFNA9) resulting in a p.Q110K substitution and a deletion c. 2814_2815delAA in MYO6 (DFNA22) causing a frameshift alteration p.R939Tfs * 2. The pathogenicity of novel coding variants in ADNSHL genes was carefully evaluated by analysis of co-segregation with phenotype in the pedigree and in light of established genotype-phenotype correlations. The frameshift deletion in MYO6 was confirmed as the causative variant for this pedigree, whereas the missense mutation in COCH had no clinical significance. The results allowed us to retrospectively identify the phenocopy in one patient that contributed to the negative finding in the linkage scan. Our clinical data also supported the emerging genotype-phenotype correlation for DFNA22.

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“…To date, 20 mutations in KCNQ4 have been reported to cause hearing loss. All are located in exons 1, 4–8 of KCNQ4 (Table 3) [4, 7, 11–25]. …”

Section: Discussionmentioning

confidence: 99%

A novel pore-region mutation, c.887G > A (p.G296D) in KCNQ4, causing hearing loss in a Chinese family with autosomal dominant non-syndromic deafness 2

et al. 2017

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BackgroundHereditary non-syndromic hearing loss is the most common inherited sensory defect in humans. The KCNQ4 channel belongs to a family of potassium ion channels that play crucial roles in physiology and disease. Mutations in KCNQ4 underlie deafness non-syndromic autosomal dominant 2, a subtype of autosomal dominant, progressive, high-frequency hearing loss.MethodsA six-generation Chinese family from Hebei Province with autosomal dominantly inherited, sensorineural, postlingual, progressive hearing loss was enrolled in this study. Mutation screening of 129 genes associated with hearing loss was performed in five family members by next-generation sequencing (NGS). We also carried out variant analysis on DNA from 531 Chinese individuals with normal hearing as controls.ResultsThis family exhibits postlingual, progressive, symmetrical, bilateral, non-syndromic sensorineural hearing loss. NGS, bioinformatic analysis, and Sanger sequencing confirmed the co-segregation of a novel mutation [c.887G > A (p.G296D)] in KCNQ4 with the disease phenotype in this family. This mutation leads to a glycine-to-aspartic acid substitution at position 296 in the pore region of the KCNQ4 channel. This mutation affects a highly conserved glutamic acid. NGS is a highly efficient tool for identifying gene mutations causing heritable disease.ConclusionsProgressive hearing loss is common in individuals with KCNQ4 mutations. NGS together with Sanger sequencing confirmed that the five affected members of this Chinese family inherited a missense mutation, c.887G > A (p.G296D), in exon 6 of KCNQ4. Our results increase the number of identified KCNQ4 mutations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-017-0396-5) contains supplementary material, which is available to authorized users.

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Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL

Cited by 14 publications

References 24 publications

A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect

A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect

Exome Sequencing Identifies a Novel Frameshift Mutation ofMYO6as the Cause of Autosomal Dominant Nonsyndromic Hearing Loss in a Chinese Family

A novel pore-region mutation, c.887G > A (p.G296D) in KCNQ4, causing hearing loss in a Chinese family with autosomal dominant non-syndromic deafness 2

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