Abstract
Ocular coloboma is a common eye malformation arising from incomplete closure of the human optic fissure during development. Multiple genetic mutations contribute to the disease process, showing extensive genetic heterogeneity and complexity of coloboma spectrum diseases. In this study, we aimed to unravel the genetic cause of a consanguineous family with unilateral coloboma and retinoschisis. The subjects were recruited and underwent specialized ophthalmologic clinical examination. A combination of whole exome sequencing (WES), homozygosity mapping, and comprehensive variant analyses was performed to uncover the causative mutation. Only one homozygous mutation (c.113 T > C, p.I38T) in RAX gene survived our strict variant filtering process, consistent with an autosomal recessive inheritance pattern. This mutation segregated perfectly in the family and is located in a highly conserved functional domain. Crystal structure modeling indicated that I38T affected the protein structure. We describe a patient from a consanguineous Chinese family with unusual coloboma, proven to harbor a novel RAX mutation (c.113 T > C, p.I38T, homozygous), expanding the phenotypic variability of ocular coloboma and RAX mutations.
Highlights
Eye development is a highly intricate and multistep process demanding well-organized genetic events during embryogenesis
As initial part of ocular coloboma component, a comprehensive ophthalmic examination was conducted in the only affected individual (IV: 2) who was a 14-year-old boy born to the consanguineous family, segregating as an autosomal recessive disorder
The examination at his first visit revealed that his visual acuity (VA) was 20/80 OD and 20/200 OS and his best corrected visual acuity (BCVA) was 20/30 OD and 20/200 OS
Summary
Eye development is a highly intricate and multistep process demanding well-organized genetic events during embryogenesis. Ocular coloboma (OC) is a common developmental structural defect defined as a segmental ocular deficiency in the iris, chorioretinal, or optic disc tissue with a prevalence of 2 to 14 per 100000 births[1], which is usually bilateral and symmetrical. Genetic causes of a large proportion of ocular coloboma are still unresolved. It is the complexity of eye development that accounts for the variety of structural eye defects, with overwhelming possibilities for disruption. A subset of familial or isolated OC cases resulted from mutations in particular genes, commonly in an autosomal recessive or dominant heritance pattern[6,7,8]. We combined whole exome sequencing (WES), homozygosity mapping, and thorough variant analysis to dissect the genetic basis, aiming to expand the genotype-phenotype correlations of ocular coloboma
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