Mutations in X-Linked RPGR Account for an Appreciable Fraction of Families With a Pedigree Consistent With Autosomal Dominant Retinitis Pigmentosa

Abstract

Purpose: : To determine the fraction of families with mutations in the X-linked RPGR gene (retinitis pigmentosa GTPase regulator) among families with findings suggestive of autosomal dominant retinitis pigmentosa (adRP). The existence of non-penetrant individuals in adRP families with PRPF31 and TOPORS mutations, and the wide range of clinical phenotypes found among "carrier" females with RPGR mutations, can obscure the distinction between X-linked and autosomal dominant inheritance in multigenerational families without male-to-male transmission.

Methods: : Thirty-five multiplex families from a cohort of 230 with findings consistent with adRP (Sullivan et al. IOVS 47:3052, 2006) were selected for RPGR testing. The 35 families had a provisional (or alternate) clinical diagnosis of adRP, a pedigree consistent with adRP, i.e., at least 3 generations of affected individuals including at least one female, but no male-to-male transmission. The families had been screened previously for mutations in genes that are common causes of adRP. Pedigrees were analyzed to determine the statistical likelihood of autosomal dominant inheritance relative to X-linked inheritance using LINKAGE with an invariant genotype at a dummy locus for each individual. Genomic DNAs were screened for mutations in RPGR, including exon 9a and ORF15, using automated fluorescent capillary DNA sequencing.

Results: : Disease-causing RPGR mutations were identified in eight of the families tested and a novel, potentially disease-causing mutation was identified in one additional family. The log likelihood ratios of autosomal dominant versus X-linked inheritance in the families with RPGR mutations ranges from -2 to 8 with a mean of 2. An additional six families in the "adRP" cohort were found previously to have RPGR mutations bringing the minimum count to 14 in 230 (6%).

Conclusions: : Mutations in RPGR account for an appreciable fraction of families with a pedigree consistent with adRP. The distinction between X-linked and autosomal disease can often be made based on clinical findings, but these observations stress the importance of considering both autosomal and X-linked genes in families with an ambiguous pedigree lacking male-to-male transmission. This also suggests that mutations in RPGR are a more common cause of RP than previously thought.

Keywords: retinal degenerations: hereditary • genetics • mutations