Elsevier

Genetics in Medicine

Volume 10, Issue 11, November 2008, Pages 797-804
Genetics in Medicine

Article
Audioprofile-directed screening identifies novel mutations in KCNQ4 causing hearing loss at the DFNA2 locus

https://doi.org/10.1097/GIM.0b013e318187e106Get rights and content
Under an Elsevier user license
open archive

Abstract

Purpose

Gene identification in small families segregating autosomal dominant sensorineural hearing loss presents a significant challenge. To address this challenge, we have developed a machine learning-based software tool, AudioGene v2.0, to prioritize candidate genes for mutation screening based on audioprofiling.

Methods

We analyzed audiometric data from a cohort of American families with high-frequency autosomal dominant sensorineural hearing loss. Those families predicted to have a DFNA2 audioprofile by AudioGene v2.0 were screened for mutations in the KCNQ4 gene.

Results

Two novel missense mutations and a stop mutation were detected in three American families predicted to have DFNA2-related deafness for a positive predictive value of 6.3%. The false negative rate was 0%. The missense mutations were located in the channel pore region and the stop mutation was in transmembrane domain S5. The latter is the first DFNA2-causing stop mutation reported in KCNQ4.

Conclusions

Our data suggest that the N-terminal end of the P-loop is crucial in maintaining the integrity of the KCNQ4 channel pore and AudioGene audioprofile analysis can effectively prioritize genes for mutation screening in small families segregating high-frequency autosomal dominant sensorineural hearing loss. AudioGene software will be made freely available to clinicians and researchers once it has been fully validated.

Keywords

KCNQ4
DFNA2
hearing loss
AudioGene v2.0
audioprofiling

Cited by (0)