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

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: (1) that the N-terminal end of the P-loop is crucial in maintaining the integrity of the KCNQ4 channel pore; and, (2) that 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 fullly validated.

Relative Time Course of Degeneration of Different Cochlear Structures in the CD/1 Mouse Model of Accelerated Aging

“…The development of stem-cell technology offers a means to repair the damaged or presbycusic cochlea (Hildebrand et al 2008) or prevent presbycusis with timely intervention. The outbred CD/1 mouse strain commonly shows accelerated presbycusis (Shone et al 1991) with hearing loss at about 4 weeks, prior to hair cell loss (Le Calvez et al 1998a, b).…”

Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL

“…20 Generally, missense mutations in KCNQ4 have been associated with more severe, earlier-onset, all-frequency SNHL, while deletions are reported to cause a milder phenotype characterized by a later age of onset affecting only high frequencies. 12,15,19,20,22 Recently, a third deletion, c.664del18, reported in a Korean family causes the deletion of six amino acids in the intra-membrane loop between the fourth and fifth (S4 and S5) transmembrane domains. 19 Baek et al (2010) verified the importance of the S4-S5 loop for proper potassium channel function.…”

“…12,14 The novel p.S269del mutation is predicted to cause the removal of a serine residue between the S5 and S6 transmembrane domains that form the channel pore, which contains a filter that selects for the passage of potassium ions in the inner ear. 15 To date, 16 mutations in KCNQ4 are associated with ADSNHL, including 11 missense, 11,12,15-24 1 nonsense, 15 1 splice-site mutation 21 and 3 deletions. 17,19,20 Of the 11 missense mutations reported, 6 are found in the P-loop and cause early-onset allfrequency hearing loss.…”

“…Carriers of the p.S269del mutation also show that severity of the loss increases with age across all frequencies. 12,15,19,20,22,25 All family members heterozygous for the p.S269del mutation were diagnosed with SNHL, indicating that this KCNQ4 mutation is highly penetrant. However, three first-degree relatives of the index case did not inherit the KCNQ4 deletion or the deafness-associated DFNA2 haplotype but inherited the normal chromosome from the parent.…”

Deaf mute or Deaf

“…Deafness can be from a mutation in a single gene or combination of mutations in different genes (Hildebrand et al, 2008). Hereditary hearing loss and deafness may be conductive, sensorineural, or a combination of both, or syndromic or nonsyndromic.…”