Homozygosity Mapping and Whole-Genome Sequencing Links a Missense Mutation in POMGNT1 to Autosomal Recessive Retinitis Pigmentosa

Abstract To identify the genetic cause in five families with autosomal recessive retinitis pigmentosa, a genetic disorder involving retinal degeneration and visual loss with high genetic heterogeneity. We performed whole-genome single nucleotide polymorphism genotyping on 35 members from the five families to map the region of homozygosity shared by all patients. Whole-genome sequencing was then conducted on one of the patients and a novel variant was identified in POMGNT1 from the homozygous region, which was confirmed by Sanger sequencing and sequenced in all family members. Mutant and wild-type POMGNT1 were expressed in heterologous cells to assess enzyme activity. A 1.8-Mb homozygous region was identified at 1p34-p33 shared by all 17 patients. Whole-genome sequencing revealed a novel missense mutation in POMGNT1 (c.359A>C, p.Leu120Arg) from this homozygous region, which was shown to co-segregate with disease phenotype. The mutant protein carrying this missense mutation showed an approximately 80% decrease in POMGNT1 enzyme activity compared with the wild type. We identified a novel mutation in POMGNT1 that causes nonsyndromic autosomal recessive retinitis pigmentosa, adding to the genetic heterogeneity of this retinal disease. POMGNT1 encodes a glycosyltransferase in O-mannosyl glycosylation and was previously found to be responsible for a group of congenital muscular dystrophies called dystroglycanopathies. Our discovery suggests the involvement of O-mannosyl glycosylation in retinitis pigmentosa and presents an instance of POMGNT1 mutation that does not involve muscular dystrophy.