Biallelic Mutation of Protocadherin-21 (pcdh21) Causes Retinal Degeneration in Humans

Abstract

Purpose: : To identify novel genes through genome-wide linkage studies of consanguineous families segregating recessive human retinal degeneration.

Methods: : Regions of common autozygosity for contiguous SNPs were sought from a genome-wide linkage study of two consanguineous pedigrees with arRP using the 10K and 50K Affymetrix GeneChip Mapping Array. Candidate genes within such regions were subsequently sequenced. DNA from probands of other families were screened for further mutations. Clinical data including electrodiagnostics, visual fields and colour fundus photography were obtained where possible.

Results: : Linkage to an interval on chromosome 10q23.1-23.3, which harboured PCDH21, was mapped in both families and subsequent sequencing of PCDH21 revealed homozygosity for two distinct frame-shifting indel mutations: c.337delG and c.1463delG. Neither was detected in 280 ethnically matched control chromosomes. Direct sequencing of a further 56 patients with recessive retinal degeneration revealed two homozygous variants, IVS3+6G>A and p.R162S. A history of myopia and night blindness in mid to late teenage years was common, with detectable field loss and loss of central vision in the third decade. The fundus features were variable though little pigment migration was seen at any age; RPE atrophy at the macula was common later in the disease.

Conclusions: : Biallelic mutation of PCDH21 is a rare cause of human recessive retinal degeneration. The gene is currently being screened in a further cohort of probands to determine the prevalence of mutations in human retinal degeneration.

Keywords: gene screening • retinal degenerations: hereditary • genetics