Genetic Profile and Mutation Spectrum of Leber Congenital Amaurosis in a Larger Indian Cohort using High Throughput Targeted Re-sequencing

ABSTRACT

The prevalence of mutations in Leber congenital amaurosis (LCA) candidate genes varies in different populations and comprehensive data from a larger Indian cohort on known candidate genes is still unavailable. Ninety-two subjects were recruited after complete ophthalmic examination and informed consent. Targeted re-sequencing of 20 candidate genes was performed using Agilent HaloPlex target enrichment assay and sequenced on Ilumina MiSeq platform. The data was analyzed using standard bioinformatics pipeline, variants annotated, validated and segregated. Genotype-phenotype correlation was performed for the mutation positive cases. Targeted NGS for the 20 candidate genes generated data with an average sequence coverage and depth of 99.03% and 134X, respectively. Mutations were identified in 61% (56/92) of the cohort, which was validated, segregated in the families and absent in 200 control chromosomes. These mutations were observed in 14/20 candidate genes and 47% (25/53) were novel. A digenic mutation was also observed. Distinct phenotypes were observed with respect to genotypes. To our knowledge, this study presents the first comprehensive mutation spectrum of LCA in a large Indian cohort. The mutation negative cases indicate scope for finding novel candidate gene(s) though mutations in deep intronic and regulatory regions cannot be ruled out.

Frequency of Mutations in 14/20 LCA Candidate Genes in The 61% (56/95) Indians With GUCY2D Gene Contributing The Highest (13%).

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