New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies

AbstractGJA8 encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions.GJA8 mutations have been linked to early onset cataracts in humans and animal models. In mice, missense mutations and homozygousGja8 deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting thatGja8 may play a role in both lens development and ocular growth. Following screening ofGJA8 in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known [p.(Thr39Arg), p.(Trp45Leu), p.(Asp51Asn), and p.(Gly94Arg)] and two novel [p.(Phe70Leu) and p.(Val97Gly)] likely pathogenic variants in seven families. Five of these co-segregated with cataracts and microphthalmia, whereas the variant p.(Gly94Arg) was identified in an individual with congenital aphakia, sclerocornea, microphthalmia and coloboma. Four missense variants of unknown or unlikely clinical significance were also identified. Furthermore, the screening ofGJA8 structural variants in a subgroup of 188 individuals identified heterozygous 1q21 microdeletions in five families with coloboma and other ocular and/or extraocular findings. However, the exact genotype –phenotype correlation of these structural variants remains to be established. Our data expand the spectrum ofGJA8 variants and associated phenotypes, confirming the importance of this gene in early eye development.

Source: Human Genetics - February 20, 2018 Category: Genetics & Stem Cells Source Type: research