GJA8-associated developmental eye disorders: a new multicentre study highlights mutational hotspots and genotype-phenotype correlations

Abstract

Variants in gap junction protein alpha 8 (GJA8), the gene encoding connexin 50 (Cx50), are primarily associated with developmental cataract, although some are associated with severe structural eye anomalies, such as aphakia (absent lens), microphthalmia (small eyes), and sclerocornea. To further define the relationship of GJA8 variants to ocular developmental disorders, we screened four large international cohorts with structural eye anomalies, including anophthalmia, microphthalmia, and coloboma (AMC) or cataracts. We identified 15 new families carrying 14 different heterozygous GJA8 variants (12 missense variants and two 1q21 microdeletions). The missense variants comprised 10 previously reported alterations in cases with eye anomalies [p.(Gly22Ser), p.(Val44Met), p.(Asp67Gly), p.(Arg76Cys), p.(Pro88Leu), p.(Gly94Glu), p.(Gly94Arg), p.(His98Arg), p.(Pro189Ser), and p.(Arg198Trp)] and two not yet linked with disease [p.(Thr39Met) and p.(Tyr66Asp)]. Their associated phenotypes ranged from isolated cataracts to a combination of microphthalmia and cataract with/without sclerocornea. Our study confirms GJA8 variants as an important source of genetic diagnoses for families with structural eye anomalies in addition to cataract and highlights specific mutational hotspots. Furthermore, we confirm an important genotype-phenotype correlation between sclerocornea and the p.(Gly94Arg) variant, and detail intra- and inter-familial phenotypic variability, which is important for clinical assessment and genetic counselling.

Fig. 1. Pedigrees of families reported in the present study.

Affected individuals in Families 1-13 carry heterozygous missense GJA8 variants. Affected individuals in Families 14 and 15 carry heterozygous 1q21 microdeletions affecting GJA8. Arrows indicate probands; “?” indicate unknown genotypes.

Fig. 2. Schematic of the GJA8 protein showing the location of variants associated with structural eye disorders.

GJA8 variants are indicated according to their amino acid positions. The functional protein domains are labelled according to Uniprot (entry ID: P48165). Previously published variants associated with developmental eye anomalies are shown above the protein schematic, and missense variants identified in the present study are marked below. The novel variants identified in the present study are indicated in red. NT N-terminal domain, TM transmembrane domain, ECL extracellular loop, ICL intracellular cytoplasmic loop, CT C-terminal domain.