Comprehensive mutation analysis by whole-exome sequencing in 41 Chinese families with Leber congenital amaurosis

Purpose: Leber congenital amaurosis (LCA) is a genetically heterogeneous disease with, to date, 19 identified causative genes. Our aim was to evaluate the mutations in all 19 genes in Chinese families with LCA.

Methods: LCA patients from 41 unrelated Chinese families were enrolled, including 25 previously unanalyzed families and 16 families screened previously by Sanger sequencing, but with no identified mutations. Genetic variations were screened by whole-exome sequencing and then validated using Sanger sequencing.

Results: A total of 41 variants predicted to affect protein coding or splicing was detected by whole-exome sequencing, and 40 were confirmed by Sanger sequencing. Bioinformatic and segregation analyses revealed 22 potentially pathogenic variants (17 novel) in 15 probands, comprised of 3 of 16 previously analyzed families and 12 of 25 (48%) previously unanalyzed families. In the latter 12 families, mutations were found in CEP290 (three probands); GUCY2D (two probands); and CRB1, CRX, RPE65, IQCB1, LCA5, TULP1, and IMPDH1 (one proband each). Based on the results from 87 previously analyzed probands and 25 new cases, GUCY2D, CRB1, RPGRIP1, CEP290, and CRX were the five most frequently mutated genes, which was similar to the results from studies in Caucasian subjects.

Conclusions: Whole-exome sequencing detected mutations in the 19 known LCA genes in approximately half of Chinese families with LCA. These results, together with our previous results, demonstrate the spectrum and frequency of mutations of the 19 genes responsible for LCA in Han Chinese individuals. Whole-exome sequencing is an efficient method for detecting mutations in highly heterogeneous hereditary diseases. Chinese Abstract.