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




A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Human Genetics

, Volume 136, Issue 1, pp 107–118

First Online: 12 November 2016Received: 09 August 2016Accepted: 07 November 2016

Abstract

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

Electronic supplementary materialThe online version of this article doi:10.1007-s00439-016-1746-7 contains supplementary material, which is available to authorized users.

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Autor: Justin A. Pater - Tammy Benteau - Anne Griffin - Cindy Penney - Susan G. Stanton - Sarah Predham - Bernadine Kielley - Je

Fuente: https://link.springer.com/







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