title: Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL.
abstract: 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.
authors: Discipline of Genetics, Faculty of Medicine, Memorial University, St John's, Newfoundland and Labrador, Canada.
authors: Nelly
authors: N
authors: Abdelfatah
authors: David A
authors: DA
authors: McComiskey
authors: Lance
authors: L
authors: Doucette
authors: Anne
authors: A
authors: Griffin
authors: Susan J
authors: SJ
authors: Moore
authors: Carol
authors: C
authors: Negrijn
authors: Kathy A
authors: KA
authors: Hodgkinson
authors: Justin J
authors: JJ
authors: King
authors: Mani
authors: M
authors: Larijani
authors: Jim
authors: J
authors: Houston
authors: Susan G
authors: SG
authors: Stanton
authors: Terry-Lynn
authors: TL
authors: Young
mesh_terms: D000595:Amino Acid Sequence; D000072259:Connexin 26; D017630:Connexins; D005260:Female; D017353:Gene Deletion; D018740:Genetic Heterogeneity; D006319:Hearing Loss, Sensorineural / Q000151:congenital / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D051656:KCNQ Potassium Channels / Q000737:chemistry / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D051656:KCNQ Potassium Channels; C117367:KCNQ4 protein, human; D000072259:Connexin 26