Truncating Variants in the Majority of the Cytoplasmic Domain of PCDH15 Are Unlikely to Cause Usher Syndrome 1F

Publication date: November 2014 Source:The Journal of Molecular Diagnostics, Volume 16, Issue 6 Author(s): Cynthia Perreault-Micale , Alexander Frieden , Caleb J. Kennedy , Dana Neitzel , Jessica Sullivan , Nicole Faulkner , Stephanie Hallam , Valerie Greger Loss of function variants in the PCDH15 gene can cause Usher syndrome type 1F, an autosomal recessive disease associated with profound congenital hearing loss, vestibular dysfunction, and retinitis pigmentosa. The Ashkenazi Jewish population has an increased incidence of Usher syndrome type 1F (founder variant p.Arg245X accounts for 75% of alleles), yet the variant spectrum in a panethnic population remains undetermined. We sequenced the coding region and intron-exon borders of PCDH15 using next-generation DNA sequencing technology in approximately 14,000 patients from fertility clinics. More than 600 unique PCDH15 variants (single nucleotide changes and small indels) were identified, including previously described pathogenic variants p.Arg3X, p.Arg245X (five patients), p.Arg643X, p.Arg929X, and p.Arg1106X. Novel truncating variants were also found, including one in the N-terminal extracellular domain (p.Leu877X), but all other novel truncating variants clustered in the exon 33 encoded C-terminal cytoplasmic domain (52 patients, 14 variants). One variant was observed predominantly in African Americans (carrier frequency of 2.3%). The high incidence of truncating exon 33 variants indicates that they are unlikel...
Source: The Journal of Molecular Diagnostics - Category: Pathology Source Type: research