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

• Published in: European Journal of Human Genetics
• Main Authors: Abdelfatah, Nelly, McComiskey, David A, Doucette, Lance, Griffin, Anne, Moore, Susan J, Negrijn, Carol, Hodgkinson, Kathy A, King, Justin J, Larijani, Mani, Houston, Jim, Stanton, Susan G, Young, Terry-Lynn
• Format: Text
• Language: English
• Published: Nature Publishing Group 2013
• Subjects: Article; Canada; Newfoundland
• Online Access: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778362; http://www.ncbi.nlm.nih.gov/pubmed/23443030; https://doi.org/10.1038/ejhg.2013.5

Autosomal dominant sensorineural hearing loss (ADSNHL) is extremely genetically heterogeneous, making it difficult to molecularly diagnose. We identified a multiplex (n=28 affected) family from the genetic isolate of Newfoundland, Canada with variable SNHL and used a targeted sequencing approach based on population-specific alleles in WFS1, TMPRSS3 and PCDH15; recurrent mutations in GJB2 and GJB6; and frequently mutated exons of KCNQ4, COCH and TECTA. We identified a novel, in-frame deletion (c.806_808delCCT: p.S269del) in the voltage-gated potassium channel KCNQ4 (DFNA2), which in silico modeling predicts to disrupt multimerization of KCNQ4 subunits. Surprisingly, 10/23 deaf relatives are non-carriers of p.S269del. Further molecular characterization of the DFNA2 locus in deletion carriers ruled out the possibility of a pathogenic mutation other than p.S269del at the DFNA2A/B locus and linkage analysis showed significant linkage to DFNA2 (maximum LOD=3.3). Further support of genetic heterogeneity in family 2071 was revealed by comparisons of audio profiles between p.S269del carriers and non-carriers suggesting additional and as yet unknown etiologies. We discuss the serious implications that genetic heterogeneity, in this case observed within a single family, has on molecular diagnostics and genetic counseling.