A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect

• DOI: 10.1007/s00439-016-1746-7
• Publication Date: 2016-11-12T09:39:23Z
• Authors: Justin A. Pater; Tammy Benteau; Anne Griffin; Cindy Penney; Susan G. Stanton; Sarah Predham; Bernadine Kielley; Jessica Squires; Jiayi Zhou; Quan Li; Nelly Abdelfatah; Darren D. O’Rielly; Terry-Lynn Young
• Keywords: Sanger sequencing; Proband; Founder effect; Compound heterozygosity

Genetic isolates provide unprecedented opportunities to identify pathogenic mutations and explore the full natural history of clinically heterogeneous phenotypes such as hearing loss. We noticed a unique audioprofile, characterized by prelingual rapid deterioration thresholds at frequencies >0.5 kHz in several adults from unrelated families island population Newfoundland. Targeted serial Sanger sequencing probands for deafness alleles (n = 23) that we previously identified this founder was negative. Whole exome four members largest family (R2010) CLDN14 (DFNB29) variant [c.488C>T; p. (Ala163Val)], likely pathogenic, sensorineural loss, autosomal recessive. Although not associated with or disease, p.(Ala163Val) has been reported uncertain significance (VUS). 169 one homozygote heterozygous carrier. Genealogical studies, cascade haplotype analysis across showed all subjects audioprofile 12) were also homozygous shared 1.4 Mb DFNB29-associated on chromosome 21. Most significantly, 175 controls revealed 1% are p.(Ala163Val), consistent major effect The youngest p.(Ala163Val)] passed newborn screening had normal up 3 years age, which then deteriorated precipitous loss >1 during first decade. Our study suggests genetic testing may be necessary at-risk children time prevent speech, language developmental delay.