Dataset Information

Comprehensive genetic screening of KCNQ4 in a large autosomal dominant nonsyndromic hearing loss cohort: genotype-phenotype correlations and a founder mutation.

ABSTRACT: The present study of KCNQ4 mutations was carried out to 1) determine the prevalence by unbiased population-based genetic screening, 2) clarify the mutation spectrum and genotype/phenotype correlations, and 3) summarize clinical characteristics. In addition, a review of the reported mutations was performed for better understanding of this deafness gene. The screening using 287 probands from unbiased Japanese autosomal dominant nonsyndromic hearing loss (ADNSHL) families identified 19 families with 7 different disease causing mutations, indicating that the frequency is 6.62% (19/287). While the majority were private mutations, one particular recurrent mutation, c.211delC, was observed in 13 unrelated families. Haplotype analysis in the vicinity of c.211delC suggests existence of a common ancestor. The majority of the patients showed all frequency, but high-frequency predominant, sensorineural hearing loss. The present study adds a new typical audiogram configuration characterized by mid-frequency predominant hearing loss caused by the p.V230E mutation. A variant at the N-terminal site (c. 211delC) showed typical ski-slope type audiogram configuration. Concerning clinical features, onset age was from 3 to 40 years old, and mostly in the teens, and hearing loss was gradually progressive. Progressive nature is a common feature of patients with KCNQ4 mutations regardless of the mutation type. In conclusion, KCNQ4 mutations are frequent among ADNSHL patients, and therefore screening of the gene and molecular confirmation of these mutations have become important in the diagnosis of these conditions.

SUBMITTER: Naito T

PROVIDER: S-EPMC3662675 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Comprehensive genetic screening of KCNQ4 in a large autosomal dominant nonsyndromic hearing loss cohort: genotype-phenotype correlations and a founder mutation.

Naito Takehiko T Nishio Shin-ya SY Iwasa Yoh-ichiro Y Yano Takuya T Kumakawa Kozo K Abe Satoko S Ishikawa Kotaro K Kojima Hiromi H Namba Atsushi A Oshikawa Chie C Usami Shin-ichi S

PloS one 20130523 5

The present study of KCNQ4 mutations was carried out to 1) determine the prevalence by unbiased population-based genetic screening, 2) clarify the mutation spectrum and genotype/phenotype correlations, and 3) summarize clinical characteristics. In addition, a review of the reported mutations was performed for better understanding of this deafness gene. The screening using 287 probands from unbiased Japanese autosomal dominant nonsyndromic hearing loss (ADNSHL) families identified 19 families wit ...[more]

PMID: 23717403

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Project description:The French Canadian population of Quebec is a unique, well-known founder population with religious, linguistic, and geographic isolation. The genetics of retinitis pigmentosa (RP) in Quebec is not well studied thus far. The purpose of our study was to establish the genetic architecture of autosomal dominant RP (adRP) and to characterize the phenotypes associated with new adRP mutations in Quebec.Sanger sequencing of the commonly mutated currently known adRP genes was performed in a clinically well-characterized cohort of 60 adRP French Canadian families. Phenotypes were analyzed by projected visual acuity (best corrected), Goldmann visual fields, optical coherence tomography (OCT), fundus autofluorescence (FAF), and ERG. The potential effect of the novel mutations was assessed using in silico bioinformatic tools. The pathogenicity of all variants was then confirmed by segregation analysis within the families, when available.We identified the causal mutation/gene in 24 of our adRP families, as 24 (40%) of 60 patients had adRP mutations in six known adRP genes. Eleven (46%) of these mutations were in RHO, four mutations (17%) were found in SNRNP200, three mutations (12.5%) in PRPH2/RDS, three mutations (12.5%) in TOPORS, two mutations (8%) in PRPF31, and one mutation (4%) in IMPDH1. Four mutations were novel. We identified new mutations in RHO (p.S270I), PRPF31 (p.R288W), IMPDH1 (p.Q318H), and TOPORS (p.H889R); the rest were previously reported. We present the genotype-phenotype characteristics of the four novel missense mutations.This is the first large screening of adRP genes in the founder population of Quebec. Our prevalence of known adRP genes is 40% in the French Canadian population, which is lower than in other adRP populations around the world, illustrating the uniqueness of the French Canadian population. Our findings are crucial in expanding the current understanding of the genotypic-phenotypic spectrum of RP and documenting the genetic architecture of our founder population.

Dataset Information

Comprehensive genetic screening of KCNQ4 in a large autosomal dominant nonsyndromic hearing loss cohort: genotype-phenotype correlations and a founder mutation.

Publications

Comprehensive genetic screening of KCNQ4 in a large autosomal dominant nonsyndromic hearing loss cohort: genotype-phenotype correlations and a founder mutation.

Similar Datasets

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