Merepa Solomon S, Reis Linda M, Damián Alejandra, Bardakjian Tanya, Schneider Adele, Trujillo-Tiebas María Jose, Ayuso Carmen, Galarza Laura Cortázar, Saez Villaverde Raquel, Ortiz-Cabrera Nelmar Valentina, Bax Dorine A, Holt Richard, Ceroni Fabiola, Edery Patrick, Grelet Maude, Riccardi Florence, Maillard Lauriane, Costakos Deborah, Plaisancié Julie, Chassaing Nicolas, Corton Marta, Semina Elena V, Ragge Nicola K
Faculty of Health, Science and Technology, School of Biological and Medical Sciences, Oxford Brookes University, Headington Campus, Gipsy Lane, Oxford, UK.
Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI, USA.
Eur J Hum Genet. 2025 Apr 30. doi: 10.1038/s41431-025-01843-8.
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.
缝隙连接蛋白α8（GJA8）是编码连接蛋白50（Cx50）的基因，其变异主要与发育性白内障相关，不过有些变异也与严重的眼部结构异常有关，如无晶状体（晶状体缺失）、小眼症（眼睛小）和角膜硬化症。为了进一步明确GJA8变异与眼部发育障碍之间的关系，我们对四个患有眼部结构异常（包括无眼症、小眼症和脉络膜缺损，即AMC）或白内障的大型国际队列进行了筛查。我们鉴定出15个携带14种不同杂合GJA8变异（12个错义变异和两个1q21微缺失）的新家族。这些错义变异包括10个先前在眼部异常病例中报道过的改变 [p.(Gly22Ser)、p.(Val44Met)、p.(Asp67Gly)、p.(Arg76Cys)、p.(Pro88Leu)、p.(Gly94Glu)、p.(Gly94Arg)、p.(His98Arg)、p.(Pro189Ser) 和 p.(Arg198Trp)] 以及两个尚未与疾病相关联的变异 [p.(Thr39Met) 和 p.(Tyr66Asp)]。它们相关的表型范围从单纯性白内障到小眼症合并白内障伴/不伴角膜硬化症。我们的研究证实，除白内障外，GJA8变异是有眼部结构异常家族遗传诊断的重要来源，并突出了特定的突变热点。此外，我们证实了角膜硬化症与p.(Gly94Arg)变异之间存在重要的基因型 - 表型相关性，并详细阐述了家族内和家族间的表型变异性，这对临床评估和遗传咨询很重要。
