title: A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect.
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.
authors.affiliation: 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.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Pater
authors.affiliation: 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.
authors.forename: Tammy
authors.initials: T
authors.lastname: Benteau
authors.affiliation: 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.
authors.forename: Anne
authors.initials: A
authors.lastname: Griffin
authors.affiliation: 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.
authors.forename: Cindy
authors.initials: C
authors.lastname: Penney
authors.affiliation: Communication Sciences and Disorders, Western University, Elborn College, 1201 Western Road, London, ON, N6G 1H1, Canada.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Stanton
authors.affiliation: 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.
authors.forename: Sarah
authors.initials: S
authors.lastname: Predham
authors.affiliation: Department of Education and Early Childhood Development, Government of Newfoundland and Labrador, St. John's, NL, A1B 4J6, Canada.
authors.forename: Bernadine
authors.initials: B
authors.lastname: Kielley
authors.affiliation: 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.
authors.forename: Jessica
authors.initials: J
authors.lastname: Squires
authors.affiliation: 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.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Quan
authors.initials: Q
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Nelly
authors.initials: N
authors.lastname: Abdelfatah
authors.affiliation: 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.|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.
authors.forename: Darren D
authors.initials: DD
authors.lastname: O'Rielly
authors.affiliation: 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.|Communication Sciences and Disorders, Western University, Elborn College, 1201 Western Road, London, ON, N6G 1H1, Canada. tlyoung@mun.ca.|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.
authors.forename: Terry-Lynn
authors.initials: TL
authors.lastname: Young
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D057167:Claudins / Q000235:genetics* / Q000378:metabolism; D003638:Deafness / Q000175:diagnosis / Q000235:genetics; D005260:Female; D018703:Founder Effect; D005786:Gene Expression Regulation; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis* / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D009523:Newfoundland and Labrador; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: D057167:Claudins; C422064:claudin 14