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

Abstract

BackgroundPediatric cataract is a clinically and genetically heterogeneous disease which is a significant cause of lifelong visual impairment and treatable blindness. Our study aims to investigate the genotype spectrum in a group of Chinese patients with pediatric cataract.MethodsWe enrolled 39 families with pediatric cataract from October 2015 to April 2016. DNA samples of the probands were analyzed by target next-generation sequencing. Variants were validated using Sanger sequencing in the probands and available family members.ResultsIn our cohort of 39 cases with different types of pediatric cataract, 23 cases were found to harbor putative pathogenic variants in 15 genes: CRYAA, CRYBA1, CRYBA4, CRYBB1, CRYGC, CRYGD, MIP, GCNT2, IARS2, NHS, BCOR, BFSP2, FYCO1, MAF, and PAX6. The mutation detection rates in the familial and sporadic cases were 75 and 47.8%, respectively. Of the 23 causative variants, over half were novel.ConclusionsThis is a rare report of systematic mutation screening analysis of pediatric cataract in a comparably large cohort of Chinese patients. Our observations enrich the mutation spectrum of pediatric cataract. Next-generation sequencing provides significant diagnostic information for pediatric cataract cases, especially when considering sporadic and subtle syndromal cases.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0828-0) contains supplementary material, which is available to authorized users.

Mutational analysis of BFSP1, CRYBB1, GALK1, and GJA8 in captive‐bred vervet monkeys (Chlorocebus aethiops)

“…According to the mutation taster, this variant is predicted to be disease‐causing (Table ). Subsequently, L174L is located in the 3rd Greek Key domain of CRYBB1 , which is within the same area where a missense mutation (D170Y) was identified in a Chinese family and reported to have an impact on the protein folding function; resulting in the development of total cataract . Therefore, the location of L174L within this domain which is near to the location of D170Y in the Chinese family, as well as its disease‐causing prediction, leads to a belief that L174L may contribute to the development of the total cataract in this vervet colony.…”

“…Subsequently, L174L is located in the 3rd Greek Key domain of CRYBB1, which is within the same area where a missense mutation (D170Y) was identified in a Chinese family and reported to have an impact on the protein folding function; resulting in the development of total cataract. 23 Therefore, the location of L174L…”

TRPM3_miR-204: a complex locus for eye development and disease

“…Most are non-synonymous including missense (~1048), nonsense (~43), splice-site (~43), and frameshift (~29) cSNVs of unknown pathogenic significance and the remainder are synonymous (~543) cSNVs (Table 1). While several nonsynonymous cSNVs are predicted in silico to be damaging/pathogenic, so far only two missense mutations (p.I65M, p.R1307T) in TRPM3 have been linked with inherited forms of human cataract [81,82]. In addition, a SNV (rs9792446 G/A) located in intron-2 of TRPM3 has been tentatively associated (p = 1.0e-7) with age-related nuclear cataract in a cohort of 2265 twins (age ≥ 50).…”

“…Thus, in addition to damaging effects on isoform-k function, the novel Ile>Met start-site may exert deleterious effects on multiple RefSeq channel isoforms by extending their N-termini with 89 novel amino-acids. Recently, a second missense mutation (c.3920G>C, p.Arg1307Thr) located in exon-29 of TRPM3 has been discovered in a Chinese nuclear family segregating pediatric cataract [82]. This heterozygous G>C transversion was not present in the ExAC database; however, in silico analysis (Polyphen-2 and SIFT score) predicted that the non-conservative p.Arg1307Thr substitution may be functionally benign and has been designated as a variant of 'uncertain significance' [82].…”

“…Recent genetic studies have discovered that mutation of the human TRPM3 gene underlies an inherited form of early-onset or pediatric cataract with or without glaucoma [81,82]. Subsequently, mutation of the human gene for microRNA-204 (miR-204) that is located within an intron of the TRPM3 gene (reminiscent of TRPM1 and miR-211) has been shown to underlie an inherited form of retinal dystrophy and ocular coloboma [83].…”