Autosomal dominant retinitis pigmentosa: prevalence of disease–causing mutations in known genes.

Abstract

Abstract: : Purpose: The prevalence of mutations in genes known to cause autosomal dominant retinitis pigmentosa (adRP) was determined in a cohort of 200 unrelated RP families with a high–likelihood of dominant inheritance. Methods: Patients and families were ascertained through retinal clinics in Houston, Dallas, Los Angeles and other cities in the United States. The families selected for testing met the following criteria: 1) diagnosis of RP and 2) either 3 or more affected generations and 1 or more affected females, or 2 or more affected generations and male–to–male transmission. These criteria were used to maximize the likelihood of autosomal dominant inheritance and minimize the likelihood of X–linked inheritance with expression in females. Probands were screened for mutations in FSCN2, HPRP3 (nt 1499–1598), IMPDH1, PRPF8 (nt 6895–7221), PRPF31, RDS, RHO and RP1 (nt 1472–3216) by either SSCP or by cycle sequencing. In addition, probands in 17 families without male–to–male transmission were screened for mutations in ORF15 of RPGR. Potential pathogenic mutations were confirmed in other affected family members when available. Pathogenicity of variants was established by exclusion from controls, and by evaluation of conservation, Blossom score and/or segregation within families. Results: Likely pathogenic mutations were found in 102 families (51%). The observed prevalence of pathogenic mutations in this cohort is FSCN2 – 0.0%, HPRP3 – 1.0%, IMPDH1 – 2.0%, PRPF8 – 3.5%, PRPF31 – 5.0%, RDS – 9.0%, RHO – 26%, and RP1 – 3.5%. In addition, pathogenic mutations in ORF15 of RPGR were found in 2 families (1.0%). Conclusions: Screening for mutations in eight genes known to cause adRP, in a cohort of adRP families ascertained in the United States, detects pathogenic variants in 50% of families. Additionally, a small fraction of "autosomal dominant" RP families have mutations in the X–linked RPGR gene. While it is possible that mutations in untested regulatory regions are responsible for disease in a small fraction of the remaining families, these data strongly suggest the presence of additional, unknown adRP genes.

Keywords: mutations • retinal degenerations: hereditary • genetics