Cone–Rod Dystrophy, Intra–Familial Variability and Incomplete Penetrance Associated With the R172W Mutation in the Peripherin/RDS Gene

Abstract

Abstract: : Purpose: To determine the underlying molecular genetic basis of a retinal dystrophy identified in a five–generation British family and to examine the phenotype and degree of intra–familial variability. Methods: Nine affected individuals underwent ophthalmological examination, colour vision testing, colour fundus photography, autofluorescence imaging, and electrophysiological assessment. The clinical notes of two additional deceased affected family members were also reviewed. Blood samples were taken for DNA extraction, with linkage analysis being performed and subsequent mutation screening of peripherin/RDS. Results: Linkage analysis established a disease interval on chromosome 6p, which harboured the retinal candidate gene, peripherin/RDS. The 3 coding exons of peripherin/RDS were subsequently screened for mutations in affected and unaffected family members. A non–conservative missense substitution, R172W, segregated uniquely in all affected subjects. The majority of subjects carrying the R172W peripherin/RDS mutation complained of reduced central vision starting in the second or third decade, with subsequent gradual deterioration of visual acuity and colour vision. Three affected individuals complained of nyctalopia. A range of macular appearances were seen, varying from a typical granular appearance to extensive macular atrophy. Autofluorescence imaging in the majority of individuals identified a highly characteristic speckled macular appearance. All affected subjects had abnormal pattern ERGs consistent with macular dysfunction and four subjects showed additional full–field ERG abnormalities, providing evidence of generalised retinal dysfunction. There was marked variation in the clinical phenotype in those individuals who carried the R172W peripherin/RDS mutation ranging from severe cone–rod dystrophy to asymptomatic individuals with normal retinal function. Conclusions: The Arg172Trp (R172W) peripherin/RDS mutation has been previously reported to cause a fully penetrant progressive macular dystrophy with high intra– and inter–familial consistency of phenotype. This is the first report describing marked intra–familial variation associated with this mutation including non–penetrance.

Keywords: retinal degenerations: hereditary • gene screening • degenerations/dystrophies