Carrier Frequency Analysis of Mutations Causing Recessive Inherited Retinal Diseases in the Israeli Population

Abstract

Purpose : Inherited Retinal Diseases (IRDs) are a group of diseases caused by mutations in over 250 genes. Previous carrier frequency calculations based on mathematical analysis and a limited number of control individuals revealed relatively high frequencies (1 of 5 individuals). The main purpose of this study was to calculate carrier frequency for the different autosomal recessive (AR) IRD mutations and genes in the Israeli population.

Methods : We created an SQL database containing information from gnomAD [including genotyping of > 5000 Ashkenazi Jewish (ASH) controls] and our cohort of >2000 families with IRDs. Carrier frequency was calculated based on allele frequency values and the Hardy-Weinberg (HW) equasion for 177 known IRD genes.

Results : We identified 457 IRD-causing mutations in 119 genes in Israeli patients and ASH controls. For the ASH subpopulation, gnomAD and HW-based data were available for 32 mutations and regression analysis showed high correlation (r-0.71, p<0.0000003), therefore allowing one to use HW-based data as a reliable estimate of carrier frequency. For the remaining subpopulations, only HW-based data were available. Overall carrier frequency per subpopulation ranges from 1 out of 2.4 to 1 out of 9.3 individuals, with the highest value obtained for the Arab-Muslim subpopulation in Jerusalem reaching an extremely high carrier rate of 45%, mainly due to founder mutations in ABCA4, CNGA3, and RDH12. Carrier frequencies per gene range from 1 out of 33 to 1 out of 12,204 individuals in the different subpopulations with ABCA4, USH2A and CNGA3, being the most common ones with average carrier frequencies of 1/33, 1/40 and 1/50 respectively. We estimate the total carrier frequency for at least one of the AR-IRD mutations in the Israeli population to be at least 33%.

Conclusions : The carrier frequency of IRD mutations in the Israeli population is relatively high with marked variability among subpopulations, and therefore these data are highly important for more reliable genetic counseling and gene screening. The high carrier frequency in some subpopulations is in-line with the prevalence of retinitis pigmentosa in Israel (1:2,200) that is much higher than worldwide reports (1:4,500).

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.