Cutis Verticis Gyrata, Retinitis Pigmentosa, and Sensorineural Deafness Syndrome is Caused by Mutation in the Cohen Syndrome Gene, Vps13b

Abstract

Purpose: : To identify the genetic basis for a syndrome characterized by microcephaly, cutis verticis gyrata (CVG), retinitis pigmentosa, cataracts, hearing loss and mental retardation (MIM #605685) previously described by us in a non-consanguineous Lebanese family.

Methods: : Genomewide homozygosity mapping (10K Array). VPS13B exons were analyzed by direct sequencing. 50 healthy controls were screened for the VPS13B mutation. RT was carried out from RNA from whole blood, followed by cDNA-specific PCR and direct sequencing. GJB2 was sequenced in one patient.

Results: : If the parents are considered non-consanguineous, >20 chromosomal regions show segregation with the phenotype. Assumption of parental consanguinity resulted in a single 7.24 Mb region on chromosome 8q22.1-q22.2 with homozygosity by descent in the patients (LOD score of 2). It comprised 46 genes, including the Cohen syndrome (CS) gene, VPS13B. We identified a homozygous splice site mutation in VPS13B (c.9406-1G>C) in both patients, activating a cryptic acceptor site in exon 52 with a consecutive 16 bp deletion in the mRNA. No GJB2 mutation was identified.

Keywords: linkage analysis • retinitis • positional cloning