Profound, prelingual nonsyndromic deafness maps to chromosome 10q21 and is caused by a novel missense mutation in the Usher syndrome type IF gene PCDH15

Abstract

We studied a consanguineous family (Family A) from the island of Newfoundland with an autosomal recessive form of prelingual, profound, nonsyndromic sensorineural hearing loss. A genome-wide scan mapped the deafness trait to 10q21-22 (max LOD score of 4.0; D10S196) and fine mapping revealed a 16 Mb ancestral haplotype in deaf relatives. The PCDH15 gene was mapped within the critical region and was an interesting candidate because truncating mutations cause Usher syndrome type IF (USH1F) and two missense mutations have been previously associated with isolated deafness (DFNB23). Sequencing of the PCDH15 gene revealed 33 sequencing variants. Three of these variants were homozygous exclusively in deaf siblings but only one of them was not seen in ethnically matched controls. This novel c.1583 T4A transversion predicts an amino-acid substitution of a valine with an aspartic acid at codon 528 (V528D). Like the two DFNB23 mutations, the V528D mutation in Family A occurs in a highly conserved extracellular cadherin (EC) domain of PCDH15 and is predicted to be more deleterious than the previously identified DFNB23 missense mutations (R134G and G262D). Physical assessment, vestibular and visual function testing in deaf adults ruled out syndromic deafness because of Usher syndrome. This study validates the DFNB23 designation and supports the hypothesis that missense mutations in conserved motifs of PCDH15 cause nonsyndromic hearing loss. This emerging genotype -phenotype correlation in USH1F is similar to that in several other USH1 genes and cautions against a prognosis of a dual sensory loss in deaf children found to be homozygous for hypomorphic mutations at the USH1F locus.

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

“…Religious and geographic isolation within small coastal fishing (outport) communities (Manion 1977) has resulted in a higher inbreeding coefficient in the NL population (Bear et al 1987, 1988; Zhai et al 2015). 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). …”

Non-clustered protocadherin

“…The mutation, splicing abnormality, frameshift, nonsense or large deletions of PCDH15 gene have been shown to cause USH1F, 63,65,66 indicating that the dysfunction of PCDH15 plays a pathogenetic role in the RP and hearing loss associated with USH1F. Moreover, null mutations in PCDH21, which is known as a photoreceptor-specific gene, 67,68 cause the RP.…”

Common variants at 10p12.31, 10q21.1 and 13q12.13 are associated with sporadic pituitary adenoma

“…The PCDH family encodes integral membrane proteins that mediate calcium-dependent cell-cell adhesion, and it has been reported to be involved in the development and progression of many cancers 17,18 . Mutations in PCDH15 result in hearing loss and Usher syndrome type 1F (USH1F) 19,20 . SNPs in this gene have also been found to be associated with lipid abnormalities 21 and immune response to smallpox vaccine 22 .…”