FAM161A Mutations In Patients With Early-onset Retinitis Pigmentosa In The United States

Abstract

Purpose: : Loss-of-function mutations in FAM161A are responsible for autosomal recessive retinitis pigmentosa (arRP) associated with the RP28 locus. In previous reports, they were identified in patients displaying both an atypically late manifestation of arRP (in a cohort from Germany) and an early-onset form of the disease (in a large cohort from Israel and the Palestinian territories, accounting for ~ 12% of the arRP cases analyzed). The aim of this study is to identify novel FAM161A mutations and better understand the genotype-phenotype relationships in an extended cohort of North American patients.

Methods: : DNA from peripheral leukocytes was extracted from 273 unrelated patients with arRP and 270 control individuals with no history of retinal degeneration. Mutational screening of PCR-amplified FAM161A coding regions and flanking intron boundaries was carried out by Sanger sequencing. Patients were clinically evaluated with an ophthalmologic examination, including Goldmann visual field testing and computerized electroretinography (ERGs). Follow-up data were collected over 10-20 years.

Results: : Three patients carried the null-mutation p.T452Sfx3, which was previously identified as a founder DNA variant in the Israeli cohort. Two compound missense variations (p.L378R/p.R562W) were found in another patient. Other DNA variants of uncertain pathogenicity were identified. ERG recordings displayed a 30 Hz flicker response in the range of 0.5 to 1.8 microvolts in all patients at first visit (age 17 to 23) and of 0.1 to 0.3 microvolts at their most recent examination. Visual fields areas to the V-4e white light were all in the range of 80 deg², except for the patient with missense mutations, who displayed a 150-fold higher value.

Conclusions: : Our data indicate that arRP due to mutations in FAM161A is responsible for a small fraction of cases in North America (1.5%), similar to the prevalence detected in Germany and unlike the data from Israel and the Palestinian territories. All patients had ERG recordings compatible with early-onset arRP. The larger visual field in the patient with missense mutations may be a consequence of a reduced FAM161A molecular impairment, compared to null mutations.

Keywords: gene screening • genetics • retinal degenerations: hereditary