Sporadic and Familial Congenital Cataracts: Mutational Spectrum and New Diagnoses Using Next‐Generation Sequencing

Abstract

Congenital cataracts are a significant cause of lifelong visual loss. They may be isolated or associated with microcornea, microphthalmia, anterior segment dysgenesis (ASD) and glaucoma, and there can be syndromic associations. Genetic diagnosis is challenging due to marked genetic heterogeneity. In this study, next‐generation sequencing (NGS) of 32 cataract‐associated genes was undertaken in 46 apparently nonsyndromic congenital cataract probands, around half sporadic and half familial cases. We identified pathogenic variants in 70% of cases, and over 68% of these were novel. In almost two‐thirds (20/33) of these cases, this resulted in new information about the diagnosis and/or inheritance pattern. This included identification of: new syndromic diagnoses due to NHS or BCOR mutations; complex ocular phenotypes due to PAX6 mutations; de novo autosomal‐dominant or X‐linked mutations in sporadic cases; and mutations in two separate cataract genes in one family. Variants were found in the crystallin and gap junction genes, including the first report of severe microphthalmia and sclerocornea associated with a novel GJA8 mutation. Mutations were also found in rarely reported genes including MAF, VIM, MIP, and BFSP1. Targeted NGS in presumed nonsyndromic congenital cataract patients provided significant diagnostic information in both familial and sporadic cases.

Clinical and genetic characteristics of Chinese patients with familial or sporadic pediatric cataract

“…Some syndromal pediatric cataracts may be subtle, with associated systemic features presenting or becoming apparent only in later childhood [8]. The sporadic case #9 carried a novel BCOR mutation associated with OFCD syndrome, but she presented with only subtle clinical features, yet her cardiac status should be monitored for signs of disease progression.…”

“…Mutations in over 318 genes associated with cataracts had been reported prior to 29 January 2018 (http://cat-map.wustl.edu/), including genes coding for crystallins, intermediate filament proteins, cytoskeleton proteins, gap junction proteins, lens membrane proteins, and lens-associated transcription factors [8]. In this study, we characterize the clinical manifestations and identify pathogenic variants in a cohort of 39 pediatric cataract cases with a variety of inheritance patterns, including a high proportion of sporadic cases in non-consanguineous families.…”

Novel phenotypes and loci identified through clinical genomics approaches to pediatric cataract

“…Fortunately, the advent of genomics tools enables the interrogation of a large number of genes simultaneously. The potential of this approach to improve the diagnostic yield in pediatric cataract has already been demonstrated in a number of studies (Gillespie et al 2014, 2016; Ma et al 2016; Musleh et al 2016). The unbiased nature of this approach has unraveled the full phenotypic potential of known cataract genes and enabled the establishment of novel syndromic and isolated cataract genes (Aldahmesh et al 2012).…”

A Missense Mutation in <i>GJA8</i> Encoding Connexin 50 in a Chinese Pedigree with Autosomal Dominant Congenital Cataract

“…NGS-based genetic diagnosis is a potential technique to clarify the marked heterogeneity on genotype and phenotype of congenital cataract, for it can be achieved in approximately 70% of familial or sporadic nonsyndromal cases (Ma et al 2016). In this study, targeted exome sequencing was successfully used to identify a c.10T>A mutation of GJA8 gene in our pedigree.…”

“…They are often translated to a variety of lens structural proteins, such as crystallin, gap junction, lens membrane proteins, intermediate filament, and ocular developmental related transcription factors (Ma et al 2016). Among these genes, crystallin genes CRYAA (crystallin alpha A), CRYAB (crystallin alpha B), CRYBA1 (crystallin beta A1), CRYBB1 (crystallin beta B1), CRYBB2 (crystallin beta B2), CRYBB3 (crystallin beta B3), CRYBA2 (crystallin beta A2), CRYBA4 (crystallin beta A4), CRYGC (crystallin gamma C), CRYGD (crystallin gamma D), and CRYGS (crystallin gamma S) contribute to approximately half of the pathogenic mutations, whereas a quarter of the mutations were derived from connexin genes GJA3 (gap junction protein alpha 3) and GJA8 (gap junction protein alpha 8) (Ren et al 2017).…”