Identification of a novel large multigene deletion and a frameshift indel inPDE6Bas the underlying cause of early-onset recessive rod–cone degeneration

Abstract

A family, with two affected identical twins with early onset recessive inherited retinal degeneration, was analyzed to determine the underlying genetic cause of pathology. Exome sequencing revealed a rare, and previously reported causative variant (c.1923_1969delinsTCTGGG; p.Asn643Glyfs*29) in thePDE6Bgene in the affected twins and their unaffected father. Further investigation, using genome sequencing, identified a novel ~7.5-kb deletion (chr4:670,405-677,862del) encompassing theATP5MEgene, part of the 5'UTR ofMYL5and a 378 bp (chr4:670,405-670,782) region from the 3'UTR ofPDE6Bin the affected twins and their unaffected mother. Both variants segregated with disease in the family. Analysis of the relative expression ofPDE6B, in peripheral blood cells, also revealed significantly lower level ofPDE6Btranscript in affected siblings compared to a normal control.PDE6Bis associated with recessive rod-cone degeneration and autosomal dominant congenital stationary night blindness. Ophthalmic evaluation of these patients showed night blindness, fundus abnormalities and peripheral vision loss, which are consistent withPDE6Bassociated recessive retinal degeneration. These findings suggest that the loss ofPDE6Btranscript resulting from the compound heterozygous pathogenic variants is the underlying cause of recessive rod-cone degeneration in the study family.