Purchase this article with an account.
Rachel M Huckfeldt, Carly Murphy, Brian Palmer Hafler, Demetrios G. Vavvas, Lucy H Young, Eric A Pierce, Emily Place; Phenotypic variability in patients with RP1 mutations. Invest. Ophthalmol. Vis. Sci. 2018;59(9):39.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Retinitis pigmentosa (RP) is a genetically hetereogeneous condition, but phenotypic variability can also exist among individuals with mutations in a single gene. Mutations in RP1 cause both autosomal dominant and autosomal recessive RP (adRP, arRP) with the majority of variants occurring in the fourth and largest of this gene’s four exons. In this retrospective case series, we evaluated whether mutations outside of exon 4 result in similar clinical phenotypes.
We identified patients evaluated at Massachusetts Eye and Ear for whom either targeted genetic testing or testing with the Genetic Eye Disease panel for retinal genes identified RP1 mutations outside of exon 4. Clinical data including visual fields, retinal imaging, and electroretinograms (ERGs) from these patients were compared to those from patients with adRP and arRP due to exon 4 mutations.
Five patients between 25 and 46 years of age were identified with mutations outside of exon 4. Two were siblings, and all had family histories consistent with autosomal recessive inheritance. Four individuals were homozygous for a previously reported RP1 mutation (c.606C>A, p.D202E) and the fifth had two novel RP1 mutations (c.126G>A, p.K42N; c.308_311delCCTA). All variants were predicted to be pathogenic and were absent from gnomAD. Three of the five patients, including the compound heterozygote, had macula-predominant disease and ERGs ranging from normal to impaired but recordable. The sibling of one of these patients had visual fields and an ERG suggesting a more typical RP-like phenotype; the fifth patient had extensive macular and peripheral atrophy with a near-extinguished ERG. In comparison, patients with dominantly or recessively inherited exon 4 mutations exhibited phenotypic features that were more characteristic of previous reports regarding RP1.
Evaluation of these patients revealed unanticipated phenotypic variability in patients with RP1 mutations falling outside of exon 4. These data expand the spectrum of disease phenotypes associated with RP1 and suggest variability in how missense mutations affect RP1 function.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
This PDF is available to Subscribers Only