Identification of Variants in Four Families With Inherited Eye Disorders by Whole Exome Sequencing

Inherited eye disorders are a significant cause of vision loss worldwide. According to the World Health Organization (WHO) estimates approximately 2.2 billion people have some degree of vision loss, but a significant proportion of these are blind since early childhood. Due to poor infrastructure for genetic diagnosis, many affected families remain genetically unexplained in underdeveloped countries, including Pakistan.

In this study, we utilized homozygosity mapping and exome sequencing to identify the genetic basis of the vision loss in four Kashmiri families that were presented with different types of eye disorders. We also performed quantitative reverse transcriptase-PCR (qRT-PCR) and measured the relative mRNA abundance of ALMS1 in blood cells of patients, carrier parents, and a healthy control.

Genetic analysis identified a novel homozygous 4 base pair frameshift deletion c.5747_5750del; p.(Ala1916Glufs*21) in ALMS1 in a family affected with Alstrom syndrome (AS), and already known variants were identified (CNGA3; c.1315C>T; p.(Arg439Trp) and FYCO1; c.2206C>T; p.(Gln736*) and c.3150 + 1G>T; p.(?)) in the remaining three families. The variant identified in the ALMS1 gene is predicted to activate nonsense mediated mRNA decay (NMD). Comparison of relative mRNA abundance of ALMS1 in patient-specific cells harboring c.5747_5750del negates the NMD activation. The results indicated the absence of NMD in patient-derived cells and therefore support the formation of a truncated ALMS1 protein in the patients with the c.5747_5750del variant.

We expanded the mutation spectrum of ALMS1 but identified known variants in FYCO1 and CNGA3 genes. We also compiled the currently known mutations in these genes to establish genotype-phenotype correlation.