New mutations in GJA8 expand the phenotype to include total sclerocornea

Abstract

This project expands the disease spectrum for mutations in GJA8 to include total sclerocornea, rudimentary lenses and microphthalmia, in addition to this gene's previously known role in isolated congenital cataracts. Ophthalmic findings revealed bilateral total sclerocornea in 3 probands, with small abnormal lenses in 2 of the cases, and cataracts and microphthalmia in 1 case. Next-generation sequencing revealed de novo heterozygous mutations affecting the same codon of GJA8 : (c.281G>A; p.(Gly94Glu) and c.280G>C; p.(Gly94Arg)) in 2 of the probands, in addition to the c.151G>A; p.(Asp51Asn) mutation we had previously identified in the third case. In silico analysis predicted all of the mutations to be pathogenic. These cases show that deleterious, heterozygous mutations in GJA8 can lead to a severe ocular phenotype of total sclerocornea, abnormal lenses, and/or cataracts with or without microphthalmia, broadening the phenotype associated with this gene. GJA8 should be included when investigating patients with the severe anterior segment abnormality of total sclerocornea.

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

“…1f), we identified the variant p.(Asp51Asn) (NM_005267.4:c.151G>A; rs864309703), which affects a highly conserved amino acid located in the ECL1 domain. This change, predicted deleterious by Polyphen-2 and SIFT, has been previously reported in a patient with bilateral microphthalmia, congenital cataracts and sclerocornea (Ma et al, 2016;Ma et al, 2018). In family 3, the mutation occurred as a de novo event in the male proband, who presented with bilateral microphthalmia with associated cataracts, anterior segment dysgenesis and persistent pupillary membranes.…”

“…No details of parental phenotype or DNA were available. Interestingly this change, predicted deleterious by SIFT and Polyphen-2 and located in the TM2 domain, is absent in gnomAD, but has been previously identified as a de novo event in a child with bilateral corneal opacification and microcornea, bilateral rudimentary lenses and bilateral glaucoma (Ma et al, 2018).…”

“…In humans, missense and frameshift mutations in GJA8 (OMIM 600897) have been associated with cataracts (Beyer et al, 2013;Yu et al, 2016). Rarely, the phenotype also includes additional ocular abnormalities, mainly microcornea and iris hypoplasia (Devi and Vijayalakshmi, 2006;Hansen et al, 2007;Hu et al, 2010;Sun et al, 2011;Prokudin et al, 2014;Ma et al, 2016), but in a few cases also microphthalmia (Ma et al, 2016) and sclerocornea (Ma et al, 2018). Interestingly, defects in the formation of the lens have also been observed (Ma et al, 2018).…”

“…Rarely, the phenotype also includes additional ocular abnormalities, mainly microcornea and iris hypoplasia (Devi and Vijayalakshmi, 2006;Hansen et al, 2007;Hu et al, 2010;Sun et al, 2011;Prokudin et al, 2014;Ma et al, 2016), but in a few cases also microphthalmia (Ma et al, 2016) and sclerocornea (Ma et al, 2018). Interestingly, defects in the formation of the lens have also been observed (Ma et al, 2018). The cataracts described in these individuals vary in both their location (e.g., nuclear, zonular, lamellar or total) and appearance (e.g., total, pulverulent or dense).…”

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

“…[Gly94Arg] and c.281G>A p.[Gly94Glu], NM_005267.4), in singleton cases with severe lens developmental abnormalities, sclerocornea and microcornea (Ma et al 2018), supports a more fundamental role for GJA8 in human lens development. Moreover, these findings suggest that specific variants in GJA8 give rise to phenotypes overlapping with those caused by genetic variants of FOXE3 (Plaisancie et al 2018a).…”