Genetic Analysis of Achromatopsia in Jewish and Muslim Patients Revealed One Common Allele and 2 Novel Mutations in the CNGA3 Gene

Abstract

Methods: : Clinical evaluation included detailed family history, a full ophthalmologic exam, assessment of refractive error, color vision testing and full-field electroretinography (ERG). Blood samples were collected from the patients and the DNA was extracted. Genomic DNA was evaluated for mutations in the CNGA3 gene by sequencing and for homozygosity using the Affymetrix whole genome 10K SNP arrays.

Results: : Nineteen families with AR achromatopsia (9 Jewish and 10 Muslim) were recruited for this study. In addition, we performed a whole genome 10K SNP analysis of 27 consanguineous families with the clinical diagnosis of AR cone dystrophy (CD) or cone-rod degeneration (CRD). We identified CNGA3 mutations in 14 of the families with achromatopsia (74%) and in 2 of the families which were diagnosed as CD or CRD. In total, 10 mutations (2 of which are novel) were found in this study. Surprisingly, a single missense mutation (V529M) was identified as the main cause of achromatopsia in both Oriental Jews (4/4 families, 6/8 chromosomes) and Muslims (4/10 families, 8/20 chromosomes). Haplotype analysis of the CNGA3 genomic region revealed a shared haplotype for both Jewish and Muslim V529M-harboring chromosomes along a 1Mb fragment. The second most common mutation was a 3bp deletion (c.940_942delATC) identified in five Muslim families. In addition, we identified 2 novel frameshift mutations (c.1294delG, c.126_147dup22) and 6 previously reported mutations.

Conclusions: : Our results indicate that CNGA3 is the major gene causing achromatopsia in the Israeli population. The shared V529M haplotype might indicate a founder mutation for both Jews and Muslims. Based on our results, we predict that achromatopsia is under-diagnosed in the Israeli population (and probably in other populations as well) and patients clinically diagnosed as CD or CRD with no identified mutations, should be re-evaluated as possible achromatopsia cases. The presence of one prevailing gene and a small number of frequent mutations will allow more efficient diagnosis of patients with AR cone deficiencies.

Keywords: gene screening • macula/fovea