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.
Highlights
Hearing loss is one of the most common and genetic of all human phenotypes
The Finnish and Pakistani populations have been invaluable for discovery of deafness genes as population bottlenecks and/or inbreeding increase the likelihood of inheriting recessive alleles that are identical by descent
We have determined that a known variant of uncertain significance (VUS) (CLDN14, c.488C>T, p. (Ala163Val)) is likely pathogenic, and causes a precipitous, bilateral and rapid deterioration of hearing thresholds at frequencies >0.75 kHz in children, progressing gradually in adults
Summary
Hearing loss is one of the most common and genetic of all human phenotypes. Permanent bilateral sensorineural hearing loss affects 1/500 newborns, and almost twice as many adolescents (Smith et al 1999; Morton and Nance 2006). Hum Genet (2017) 136:107–118 other recessive genes in prelingual severe cases (Yan et al 2016; Sloan-Heggen et al 2016). Sensorineural hearing loss is characterized by both degree (mild, moderate, severe or profound) and configuration (low, mid and/or high frequency) using the standard behavioral audiogram. The Finnish and Pakistani populations have been invaluable for discovery of deafness genes as population bottlenecks (genetic drift) and/or inbreeding increase the likelihood of inheriting recessive alleles that are identical by descent. These populations are often characterized by large sibships, deep genealogies and higher consanguineous rates. We have previously identified several founder deafness mutations in the NL populations (Abdelfatah et al 2013a, b; Ahmed et al 2004; Doucette et al 2009; Young et al 2001)
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