Autosomal dominant progressive sensorineural hearing loss due to a novel mutation in the KCNQ4 gene.
OBJECTIVE
To identify the genetic etiology in a family with autosomal dominant progressive sensorineural hearing loss.


METHODS
Prospective molecular genetic research study.


METHODS
Academic genetic research laboratory.


METHODS
Seventeen members of a family with dominant progressive nonsyndromic sensorineural hearing loss: 9 affected, 6 unaffected, and 2 spouses.


METHODS
Clinical data from questionnaires, interviews, serial audiograms, and medical records; genetic data from genome-wide linkage analysis and candidate gene mutation analysis.


METHODS
Symptoms, age at onset, serial audiometric data, and the presence or absence of a deafness-associated mutation.


RESULTS
Affected individuals in this family presented with autosomal dominant nonsyndromic high-frequency progressive sensorineural hearing loss, with age at onset ranging from 1 to 21 years. Genome-wide linkage analysis of single-nucleotide polymorphisms yielded evidence of linkage to an 18.9-Mb region on chromosome 1p34-p36, with a multipoint logarithm of odds score of 3.6. This interval contains a known deafness gene, KCNQ4, which underlies DNFA2 deafness. Sequencing of the 14 coding exons and intron-exon junctions of KCNQ4 revealed a novel heterozygous missense mutation, c.859G>C, p.Gly287Arg. The mutation disrupts the highly conserved GYG motif (glycine-tyrosine-glycine) of the phosphate-binding loop, hypothesized to be critical in maintaining pore structure and function. All 274 controls were negative for the mutation.


CONCLUSIONS
Autosomal dominant high-frequency hearing loss is genetically heterogeneous, and linkage analysis is an efficient means of identifying the etiology in larger families. Deafness in this family is caused by a novel mutation in KCNQ4.
Department of Otolaryngology-Head and Neck Surgery, University of Michigan Health System, Ann Arbor, 48109-5241, USA.
Jameson
J
Arnett
Sarah B
SB
Emery
Theresa B
TB
Kim
Angelique K
AK
Boerst
Kwanghyuk
K
Lee
Suzanne M
SM
Leal
Marci M
MM
Lesperance
D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D015994:Incidence; D051656:KCNQ Potassium Channels / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D012720:Severity of Illness Index; D017678:Sex Distribution; D055815:Young Adult
D051656:KCNQ Potassium Channels; C117367:KCNQ4 protein, human
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