Referenced in: none

Automatically associated channels: Kv7.4

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

Authors: Michael S Hildebrand, Dylan Tack, Sarah J McMordie, Adam DeLuca, In Ae Hur, Carla Nishimura, Patrick Huygen, Thomas L Casavant, Richard J H Smith

Journal, date & volume: Genet. Med., 2008 Nov , 10, 797-804

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/18941426

Abstract
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.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.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.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.