Abstract
Purpose :
Variants in more than 260 different genes have been linked to hereditary retinal diseases, thus making comprehensive genomic approaches mandatory for accurate diagnosis. We explored the genetic landscape of hereditary retinal disorders in consanguineous families from North-Western Pakistan, harboring a population of approximately 35 million inhabitants that remains relatively isolated and highly inbred (~50% consanguinity).
Methods :
We leveraged on the high degree of consanguinity in 32 North-Western Pakistani families by applying genome-wide high-density SNP genotyping followed by targeted Sanger sequencing of candidate genes lying inside the autozygous intervals. In addition, we performed whole exome sequencing (WES) on at least one proband per family. The PLINK software was used for analysing SNP genotype data, while WES data were analysed using our in-house computational pipeline. Autozygosity mapping was performed by using AutoMap. Finally, Sanger sequencing was used to validate presence of the variants identified by WES and for co-segregation analysis.
Results :
We identified 10 novel and 11 previously-reported variants in a total of 17 different genes (ABCA4, AIPL1, BBS2, CNGA1, CNGA3, CNGB3, CRB1, LCA5, MKKS, NMNAT1, MYO7A, PAX6, PDE6B, RPE65, SLC6A6, SPATA7, and TULP1), already known to cause inherited retinal diseases. In spite of all families being consanguineous, heterozygosity was detected in two families. All homozygous pathogenic variants were detected inside an autozygous interval ≥2.0 Mb in size. Putative founder variants were observed in the ABCA4 (NM_000350.2:c.214G>A; p.Gly72Arg; 10 families), CRB1 (NM_201253.2:c.1459T>C; p.Ser487Pro; 3 families) and in the NMNAT1 genes (NM_022787.3:c.25G>A; p.Val9Met; 2 families).
Conclusions :
Geographic isolation and sociocultural tradition of intrafamilial matings in North-Western Pakistan favor both the clinical manifestation of rare “generic” variants and the prevalence of founder mutations
This is a 2020 ARVO Annual Meeting abstract.