High-Throughput Genetic Screening of 51 Pediatric Cataract Genes Identifies Causative Mutations in Inherited Pediatric Cataract in South Eastern Australia

Abstract

Pediatric cataract is a leading cause of childhood blindness. This study aimed to determine the genetic cause of pediatric cataract in Australian families by screening known disease-associated genes using massively parallel sequencing technology. We sequenced 51 previously reported pediatric cataract genes in 33 affected individuals with a family history (cases with previously known or published mutations were excluded) using the Ion Torrent Personal Genome Machine. Variants were prioritized for validation if they were predicted to alter the protein sequence and were absent or rare with minor allele frequency <1% in public databases. Confirmed mutations were assessed for segregation with the phenotype in all available family members. All identified novel or previously reported cataract-causing mutations were screened in 326 unrelated Australian controls. We detected 11 novel mutations in GJA3, GJA8, CRYAA, CRYBB2, CRYGS, CRYGA, GCNT2, CRYGA, and MIP; and three previously reported cataract-causing mutations in GJA8, CRYAA, and CRYBB2. The most commonly mutated genes were those coding for gap junctions and crystallin proteins. Including previous reports of pediatric cataract-associated mutations in our Australian cohort, known genes account for >60% of familial pediatric cataract in Australia, indicating that still more causative genes remain to be identified.

Identification of novel mutations causing pediatric cataract in Bhutan, Cambodia, and Sri Lanka

“…This equates to a rate of 18% (6/33) of cataract patients from the region having disease-causing mutations in known cataract-causing genes, and 30% if the possibly solved cases are included. This is substantially lower than the rates of 60%-70% reported in case series of European descent (Gillespie et al, 2014;Javadiyan et al, 2017;Ma et al, 2016). This difference remains evident even when compared with our previous study of Australian patients screened using the same gene panel, the same sequencing methodology, and the same variant filtering criteria, which found a success rate of 62% (Javadiyan et al, 2017).…”

“…This is substantially lower than the rates of 60%–70% reported in case series of European descent (Gillespie et al., ; Javadiyan et al., ; Ma et al., ). This difference remains evident even when compared with our previous study of Australian patients screened using the same gene panel, the same sequencing methodology, and the same variant filtering criteria, which found a success rate of 62% (Javadiyan et al., ). Gene discovery for this disease has predominantly been undertaken in patients of European descent and it is clear from this study that there remain novel genes to discover for inherited pediatric cataract in non‐European populations.…”

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

“…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].…”

“…MIP was mutated in three cases, representing the second most commonly mutated gene in our cohort. Interestingly, no gap junction protein-encoding genes were identified in our cohort, although they are frequently reported in non-syndromic pediatric cataract [25, 26]. …”

“…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.…”