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

Detailed Clinical Features of Deafness Caused by a Claudin-14 Variant

“…Until Pater et al reported the progression of HL [29], the phenotype of DFNB29 was associated with non-progressive, congenital or prelingual HL with a variable degree of severity [13,26,27,28]. In this report, serial audiograms showed hearing deterioration especially at low frequencies (125 to 500 Hz).…”

“…In clear contrast to this, variants of CLDN14 account for 2.25% of autosomal recessive HL in the Pakistani population. In this study, the patient was identified from a non-consanguineous family and the parents of the proband were from a geographically remote area, whereas almost all of the previous reports were from consanguineous families [13,27,28,29]. As no pathogenic CLDN14 variants were found in our cohort, but one HL patient with a homozygous CLDN14 variant was identified, it is necessary to consider such rare HL cases.…”

“…To date, nine different variants in CLDN14 [13,26,27,28,29] have been reported to cause HL in the Pakistani, Greek, and Canadian populations. Seven of the nine variants were reported from Pakistani consanguineous families.…”

A Novel Nonsense Mutation (c.414G>A; p.Trp138*) in CLDN14 Causes Hearing Loss in Yemeni Families: A Case Report

“…While most of the variants in CLDN14 that lead to hearing loss in different populations were missense variants ( Supplementary Table 3 ), nonsense variants were only found in this study and in one family from Pakistan (Lee et al, 2012). Variants of CLDN14 have been previously associated with hearing loss in Canada, Pakistan, India and Morocco (Wilcox et al, 2001; Bashir et al, 2010; Lee et al, 2012; Bashir et al, 2013; Charif et al, 2013; Pandey et al, 2017; Pater et al, 2017) ( Supplementary Table 3 ). In addition, some studies showed the absence of variants in the CLDN14 gene for other populations such as Tunisia, Turkey and China (Uyguner et al, 2003; Belguith et al, 2009; Lu et al, 2018).…”

“…This is the second documented evidence for a founder variant in the CLDN14 gene. The first founder effect has been reported for the c.488C>T variant that was predominant in the island population of Newfoundland (Pater et al, 2017).…”