Journal article
Audioprofile-directed screening identifies novel mutations in KCNQ4 causing hearing loss at the DFNA2 locus
Genetics in medicine, Vol.10(11), pp.797-804
11/2008
DOI: 10.1097/GIM.0b013e318187e106
PMCID: PMC3337550
PMID: 18941426
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.
Details
- Title: Subtitle
- Audioprofile-directed screening identifies novel mutations in KCNQ4 causing hearing loss at the DFNA2 locus
- Creators
- Michael S Hildebrand - Department of Otolaryngology - Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USADylan Tack - Department of Electrical and Computer Engineering, The University of Iowa, Iowa City, Iowa 52242, USASarah J McMordie - Department of Otolaryngology - Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USAAdam DeLuca - Department of Electrical and Computer Engineering, The University of Iowa, Iowa City, Iowa 52242, USAIn Ae Hur - Department of Electrical and Computer Engineering, The University of Iowa, Iowa City, Iowa 52242, USACarla Nishimura - Department of Otolaryngology - Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USAPatrick Huygen - Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The NetherlandsThomas L Casavant - Department of Electrical and Computer Engineering, The University of Iowa, Iowa City, Iowa 52242, USARichard J H Smith - Department of Otolaryngology - Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Genetics in medicine, Vol.10(11), pp.797-804
- DOI
- 10.1097/GIM.0b013e318187e106
- PMID
- 18941426
- PMCID
- PMC3337550
- NLM abbreviation
- Genet Med
- ISSN
- 1098-3600
- eISSN
- 1530-0366
- Grant note
- R01 DC003544-14 || DC / National Institute on Deafness and Other Communication Disorders : NIDCD
- Language
- English
- Date published
- 11/2008
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Center for Bioinformatics and Computational Biology; Otolaryngology; Internal Medicine; Ophthalmology and Visual Sciences
- Record Identifier
- 9984006346002771
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