Nonsyndromic Retinitis Pigmentosa in the Ashkenazi Jewish Population: Genetic and Clinical Aspects

Abstract

Purpose : Nonsyndromic retinitis pigmentosa (RP) is the most common inherited retinal disease, with a prevalence estimated at 1:5,000 in Europe and the USA and 1:2,230 in the Jewish population in Israel. The higher prevalence of RP in the Jewish population results mainly from intra-community marriages. The Ashkenazi Jewish (AJ) population was genetically isolated for many generations and therefore many founder mutations in this population are known to cause various autosomal recessive diseases. The purpose of the current study is to analyze the genetic and clinical findings in RP patients of AJ descent, aiming to identify genotype-phenotype correlations.

Methods : 226 RP patients who reported AJ origin of both parents were included. Direct mutation screening by Sanger sequencing was performed to detect specific founder mutations. Ophthalmologic analysis includes visual acuity (VA) testing, visual field, electroretinography (ERG), and imaging.

Results : The causative mutation was identified in 36% of families. The most prevalent RP-causing mutations in our cohort are the previously described Alu insertion (c.1297_8ins353, p.K433Rins31*) in MAK (35% of cases with a known genetic cause for RP) and c.124A>G, p.K42E in DHDDS (34%). In addition, disease-causing mutations were identified in the following genes: BBS2, CNGB1, EYS, FAM161A, HGSNAT, NR2E3, PRPH2, RHO, RP2, RPE65 and RPGR. Analysis of clinical parameters of patients with these common founder mutations revealed that on average patients with biallelic MAK mutations had a later age of onset and a milder retinal phenotype based on VA testing and cone-flicker ERG analysis compared to patients with biallelic DHDDS mutations.

Conclusions : Our AJ cohort of RP patients is the largest reported to date. Our results show a substantial difference in the genetic causes for RP in the AJ population compared to cohorts of other populations, mainly a large proportion of AR cases and a unique composition of causative genes. The most prevalent RP-causing genes in our cohort, MAK and DHDDS, were not described as major causative genes in other (non-Jewish) populations. The clinical data analysis shows that the phenotype of the MAK group of patients is less severe than that of DHDDS patients.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.