title: 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 T>A 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.
authors.affiliation: Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St John's, Newfoundland and Labrador, Canada.
authors.forename: Lance
authors.initials: L
authors.lastname: Doucette
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Merner
authors.forename: Sandra
authors.initials: S
authors.lastname: Cooke
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ives
authors.forename: Dante
authors.initials: D
authors.lastname: Galutira
authors.forename: Vanessa
authors.initials: V
authors.lastname: Walsh
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.forename: Linda
authors.initials: L
authors.lastname: MacLaren
authors.forename: Tracey
authors.initials: T
authors.lastname: Cater
authors.forename: Bridget
authors.initials: B
authors.lastname: Fernandez
authors.forename: Jane S
authors.initials: JS
authors.lastname: Green
authors.forename: Edward R
authors.initials: ER
authors.lastname: Wilcox
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Shotland
authors.forename: Larry
authors.initials: L
authors.lastname: Shotland
authors.forename: Xiaoyan Cindy
authors.initials: XC
authors.lastname: Li
authors.forename: X C
authors.initials: XC
authors.lastname: Li
authors.forename: Ming
authors.initials: M
authors.lastname: Lee
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.forename: Terry-Lynn
authors.initials: TL
authors.lastname: Young
mesh_terms: D001301:Audiometry, Pure-Tone; D001483:Base Sequence; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics*; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D003241:Consanguinity; D004252:DNA Mutational Analysis; D003638:Deafness / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D005843:Geography; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D009523:Newfoundland and Labrador; D010375:Pedigree
chemical_list: C498835:CDHR15, human; D000070585:Cadherin Related Proteins; D015820:Cadherins