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Hum Genet. 2017 Jan;136(1):107-118. doi: 10.1007/s00439-016-1746-7. Epub 2016 Nov 12.

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

Author information

1
Craig L. Dobbin Genetics Research Centre, Discipline of Genetics, Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, A1B 3V6, Canada.
2
Communication Sciences and Disorders, Western University, Elborn College, 1201 Western Road, London, ON, N6G 1H1, Canada.
3
Department of Education and Early Childhood Development, Government of Newfoundland and Labrador, St. John's, NL, A1B 4J6, Canada.
4
Molecular Diagnostic Laboratory, Eastern Health, Craig L. Dobbin Genetics Research Centre, Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, A1B 3V6, Canada.
5
Craig L. Dobbin Genetics Research Centre, Discipline of Genetics, Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, A1B 3V6, Canada. tlyoung@mun.ca.
6
Communication Sciences and Disorders, Western University, Elborn College, 1201 Western Road, London, ON, N6G 1H1, Canada. tlyoung@mun.ca.
7
Molecular Diagnostic Laboratory, Eastern Health, Craig L. Dobbin Genetics Research Centre, Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, A1B 3V6, Canada. tlyoung@mun.ca.

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.

PMID:
27838790
PMCID:
PMC5215284
DOI:
10.1007/s00439-016-1746-7
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Compliance with ethical standards Funding This work was supported by a grant from the Canadian Institutes for Health Research-Regional Partnership Program with the Research and Development Corporation of Newfoundland and Labrador, the Canadian Foundation for Innovation (New Investigator Award no. 9384 and Leaders Opportunity Fund no. 13120) and Genome Canada (Atlantic Medical Genetics and Genomics Initiative). The authors also gratefully acknowledge financial support from the Janeway Children’s Hospital Foundation, Memorial University and the Government of Newfoundland and Labrador. N.A. is a CIHR-RPP Fellowship awardee. Conflict of interest The authors declare that they have no conflict of interest.

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