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Alan Ma, John R Grigg, Bruce Bennetts, Robyn V Jamieson; Congenital cataracts: new diagnoses using next-generation sequencing in sporadic and familial cases.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4835.
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There is marked genetic heterogeneity in congenital cataracts. Cases are familial or sporadic and provision of genetic information is especially difficult in sporadic cases. Apparently non-syndromic cases may have a subtle syndromic diagnosis. To improve genetic diagnosis, we applied a next-generation sequencing (NGS) strategy in a large Australian cohort of familial and sporadic congenital cataract cases.
We studied 22 familial and 24 sporadic apparently non-syndromic congenital cataract probands. These patients were seen in the genetic eye clinic of a major referral centre over a period of 12 years. The TruSeq Custom Amplicon and TruSight One (Illumina Inc., CA, USA) NGS platforms were used to examine 32 cataract-associated genes. Sanger sequencing was performed for variant confirmation and segregation studies.
We identified pathogenic variants in 73% of familial and 68% of sporadic congenital cataract cases. In almost two-thirds (20/33) of these cases, this resulted in new information about the diagnosis and/or inheritance pattern. This included one family where a mutation in a different cataract gene (MAF) was found in the affected father, with confirmed paternity, compared with the causative disease gene (NHS) identified in his two sons. The majority of familial cases were due to autosomal dominant mutations in crystallin or gap junction genes, with two autosomal recessive cases due to mutations in these genes, and two families were found to have X-linked NHS mutations. Sporadic cases were mostly due to de novo autosomal dominant mutations in a several genes including crystallins, gap junctions, MAF, MIP and VIM and there were two de novo X-linked BCOR cases. Two novel missense mutations on the same allele were found in CRYBB2 in a sporadic case, and in another family we identified the first “run-on” mutation affecting CRYBB3. Severe microphthalmia and sclerocornea, with cataracts, was associated with a novel GJA8 mutation. PAX6 mutations were identified in two patients with complex and variable cataract phenotypes.
Our results demonstrate that targeted NGS in presumed non-syndromic congenital cataract patients provided new diagnostic and/or inheritance information in almost two-thirds of cases. This led to improvements in management and genetic information, and illustrates the important emerging role of NGS in patient care in congenital cataracts.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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