Targeted Exome Sequencing of Congenital Cataracts Related Genes: Broadening the Mutation Spectrum and Genotype–Phenotype Correlations in 27 Chinese Han Families

Abstract

Congenital cataract is the most frequent inherited ocular disorder and the most leading cause of lifelong visual loss. The screening of pathogenic mutations can be very challenging in some cases, for congenital cataracts are clinically and genetically heterogeneous diseases. The aim of this study is to investigate the mutation spectrum and frequency of 54 cartaract-associated genes in 27 Chinese families with congenital cataracts. Variants in 54 cataract-associated genes were screened by targeted next-generation sequencing (NGS) and then validated by Sanger sequencing. We identified pathogenic variants in 62.96% (17/27) of families, and over 52.94% (9/17) of these variants were novel. Among them, three are splicing site mutations, four are nonsense mutations, seven are missense mutations, two are frame shift mutations and one is intronic mutation. This included identification of: complex ocular phenotypes due to two novel PAX6 mutations; progressive cortical cataract and lamellar cataract with lens subluxation due to two novel CRYGS mutations. Mutations were also found in rarely reported genes including CRYBA4, CRYBA2, BFSP1, VIM, HSF4, and EZR. Our study expands the mutation spectrum and frequency of genes responsible for congenital cataracts. Targeted next-generation sequencing in inherited congenital cataract patients provided significant diagnostic information.

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

“…The mutation detection rate of the familial cases in our study was 75%, comparable to that published recently in familial patients from the UK (75%) [26] and another Australian cohort (73%) [8]. The mutation detection rate for familial cases in our cohort was much higher than that published recently in two studies in Chinese familial patients, with mutation pick-up rates of 50 and 64% [32, 33]. The mutation detection rate for sporadic cases in our study was 47.8%, lower than reported in sporadic patients from Australia (68%) and Saudi Arabia (62.5%) [8, 12].…”

“…We investigated 16 familial and 23 sporadic cases with pediatric cataract in the Chinese population and achieved an overall mutation detection rate of 58.97%, which is almost identical to those reported in similar studies of patients from South Eastern Australia (62%) [25], China (62.96%) [32], and Saudi Arabia(58%) [12], including zero, 7.4 and 23% of sporadic cases, respectively. The mutation detection rate of the familial cases in our study was 75%, comparable to that published recently in familial patients from the UK (75%) [26] and another Australian cohort (73%) [8].…”

“…In recent years, multiple cataract-targeted gene panels have been developed with detection rates of 26–75% [8, 12, 25, 26, 32–34]. We investigated 16 familial and 23 sporadic cases with pediatric cataract in the Chinese population and achieved an overall mutation detection rate of 58.97%, which is almost identical to those reported in similar studies of patients from South Eastern Australia (62%) [25], China (62.96%) [32], and Saudi Arabia(58%) [12], including zero, 7.4 and 23% of sporadic cases, respectively.…”

Next generation sequencing‐based molecular diagnosis in familial congenital cataract expands the mutational spectrum in known congenital cataract genes

“…Sanger sequencing confirmed five different pathogenic variants in six families. The obtained detection rate of ~55% is comparable to those reported in other NGS‐CC studies, which range from 58% to 70% (Gillespie et al, ; Ma et al, ; Patel et al, ; Zhai et al, ).…”

“…Next generation sequencing (NGS) has recently emerged as a powerful tool for the analysis of multiple genes at a time and has begun to replace Sanger sequencing for efficient genetic screening in genetically heterogeneous diseases as CC (Strande & Berg, ). Recently, several groups have successfully applied NGS for the molecular diagnosis of CC patients from different ethnic groups and their results indicate that NGS is an efficient strategy for CC diagnosis, with mutation detection rates ranging from 42% to 80% (Gillespie et al, ; Javadiyan et al, ; Ma et al, ; Musleh et al, ; Zhai et al, ). Differences in diagnostic rates are probably related to diverse factors including sample size, inclusion of sporadic versus familial cases, or ethnicity of analyzed populations.…”