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.
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.
Authors: K Verhoeven; L Van Laer; K Kirschhofer; P K Legan; D C Hughes; I Schatteman; M Verstreken; P Van Hauwe; P Coucke; A Chen; R J Smith; T Somers; F E Offeciers; P Van de Heyning; G P Richardson; F Wachtler; W J Kimberling; P J Willems; P J Govaerts; G Van Camp Journal: Nat Genet Date: 1998-05 Impact factor: 38.330
Authors: P J Coucke; P Van Hauwe; P M Kelley; H Kunst; I Schatteman; D Van Velzen; J Meyers; R J Ensink; M Verstreken; F Declau; H Marres; K Kastury; S Bhasin; W T McGuirt; R J Smith; C W Cremers; P Van de Heyning; P J Willems; S D Smith; G Van Camp Journal: Hum Mol Genet Date: 1999-07 Impact factor: 6.150
Authors: C Kubisch; B C Schroeder; T Friedrich; B Lütjohann; A El-Amraoui; S Marlin; C Petit; T J Jentsch Journal: Cell Date: 1999-02-05 Impact factor: 41.582
Authors: Mazen W Karaman; Susan Groshen; Chi-Chiang Lee; Brian L Pike; Joseph G Hacia Journal: Nucleic Acids Res Date: 2005-02-18 Impact factor: 16.971
Authors: A Eliot Shearer; Adam P DeLuca; Michael S Hildebrand; Kyle R Taylor; José Gurrola; Steve Scherer; Todd E Scheetz; Richard J H Smith Journal: Proc Natl Acad Sci U S A Date: 2010-11-15 Impact factor: 11.205
Authors: W Daniel Walls; Hideaki Moteki; Taylor R Thomas; Shin-Ya Nishio; Hidekane Yoshimura; Yoichiro Iwasa; Kathy L Frees; Carla J Nishimura; Hela Azaiez; Kevin T Booth; Robert J Marini; Diana L Kolbe; A Monique Weaver; Amanda M Schaefer; Kai Wang; Terry A Braun; Shin-Ichi Usami; Peter G Barr-Gillespie; Guy P Richardson; Richard J Smith; Thomas L Casavant Journal: Hum Genet Date: 2020-05-07 Impact factor: 4.132
Authors: Robert W Eppsteiner; A Eliot Shearer; Michael S Hildebrand; Kyle R Taylor; Adam P Deluca; Steve Scherer; Patrick Huygen; Todd E Scheetz; Terry A Braun; Thomas L Casavant; Richard J H Smith Journal: Otolaryngol Head Neck Surg Date: 2012-07-11 Impact factor: 3.497
Authors: Jameson Arnett; Sarah B Emery; Theresa B Kim; Angelique K Boerst; Kwanghyuk Lee; Suzanne M Leal; Marci M Lesperance Journal: Arch Otolaryngol Head Neck Surg Date: 2011-01
Authors: Nelly Abdelfatah; David A McComiskey; Lance Doucette; Anne Griffin; Susan J Moore; Carol Negrijn; Kathy A Hodgkinson; Justin J King; Mani Larijani; Jim Houston; Susan G Stanton; Terry-Lynn Young Journal: Eur J Hum Genet Date: 2013-02-27 Impact factor: 4.246
Authors: Michael S Hildebrand; Adam P DeLuca; Kyle R Taylor; David P Hoskinson; In Ae Hur; Dylan Tack; Sarah J McMordie; Patrick L M Huygen; Thomas L Casavant; Richard J H Smith Journal: Laryngoscope Date: 2009-11 Impact factor: 3.325
Authors: Kyle R Taylor; Adam P Deluca; A Eliot Shearer; Michael S Hildebrand; E Ann Black-Ziegelbein; V Nikhil Anand; Christina M Sloan; Robert W Eppsteiner; Todd E Scheetz; Patrick L M Huygen; Richard J H Smith; Terry A Braun; Thomas L Casavant Journal: Hum Mutat Date: 2013-02-19 Impact factor: 4.878
Authors: Michael S Hildebrand; Dylan Tack; Adam Deluca; In Ae Hur; Jana M Van Rybroek; Sarah J McMordie; Ann Muilenburg; David P Hoskinson; Guy Van Camp; Myles L Pensak; Ian S Storper; Patrick L M Huygen; Thomas L Casavant; Richard J H Smith Journal: Am J Med Genet A Date: 2009-02 Impact factor: 2.802