Investigation of Genetic Causes of Developmental Eye Disorders in Consanguineous Families

Abstract

Inherited eye disorders constitute a diverse group of genetic conditions that affect the structure and function of the visual system during development. These disorders often leading to significant visual impairments or blindness and are classified into different types depending on clinical features presented by the patients. The present study is aimed to decipher the genetic basis of three common inherited eye disorders including cone and rod dystrophy (CORD), stargardt disease (STGD) and primary congenital glaucoma (PCG). For this purpose, four consanguineous Pakistani families were recruited, and genetic analysis was performed to identify disease-causing variants. Four genes (ABCA4, CNGA3, CNGB3 and RPGRIP1) were sequenced in family A, B and D and a single gene (CYP1B1) was sequenced in family C with PCG. Sequence analysis identified two heterozygous variants c.1694C>T (p.T565M) and c. 1678A>T (p.R560W) in family A, a homozygous deletion c.1298_1298delT (p. L433Wfs*32) and two polymorphisms g.49583T>A and c.3288G>A in family B, two non-pathogenic homozygous variants c.142C>G (p.R48G) and c. 355G>T (p.A119S) in family C and one heterozygous variant c.6004A>T (p.S2002C) in family D. The p.T565M variant identified in family A is present in cGMP binding site and modeling of protein indicates the effect of variant on binding of cGMP with CNGA3. A homozygous deletion c.1298_1298delT in family B results in the pre termination codon which results in the formation of truncated protein. It can be concluded that c.1298_1298delT (p. L433Wfs*32) is responsible for CORD in affected individual of family B. The c.6004A>T (p.S2002C) variant is present in NBD2 motif of ABCA4 that is expected to affect its interaction with the respective substrate. The 3D structure analysis of ABCA4 revealed that p.S2002C variant affects the proper folding of protein, which ultimately disrupts the structure. However, current data could not identify the disease causing mutation in two families (Family C and D) and further research will be required to find the disease-causing variants in the respective families.