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.
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Acknowledgements
We thank family members for participating and Drs S Kirby, T Batten and B Fernandez for help with clinical recruitment. This work was supported by grants from the Canadian Institutes of Health Research (CIHR MOP-66974), the Canadian Foundation for Innovation (New Investigator Award no. 9384; Leaders Opportunity Fund no.13120) and Genome Canada (Atlantic Medical Genetics and Genomics Initiative) to TLY. We gratefully acknowledge financial support from the Janeway Children’s Hospital Foundation, Memorial University IRIF and the Government of Newfoundland and Labrador. We also thank the Canadian Hard of Hearing Association-NL chapter for their continued support. TLY is a CIHR salary awardee; NA is a CIHR-RPP fellowship awardee.
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Abdelfatah, N., McComiskey, D., Doucette, L. et al. Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL. Eur J Hum Genet 21, 1112–1119 (2013). https://doi.org/10.1038/ejhg.2013.5
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DOI: https://doi.org/10.1038/ejhg.2013.5
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