Mutation Analysis of 3 Genes in Patients With Leber Congenital Amaurosis

Abstract

To assess the frequency of mutations in the CRX, GUCY2D, and RPE65 genes in patients with Leber congenital amaurosis (LCA). Patients: One hundred seventy-six probands with a clinical diagnosis of LCA were from 9 countries, with the largest subgroup being 39 probands from India. Methods: Samples were screened with single-strand conformation polymorphism analysis followed by DNA sequencing of 3 genes (CRX, GUCY2D, and RPE65) known to be associated with LCA. Results: Of the 176 probands, 28 (15.9%) harbored possible disease-causing mutations. The relative contribution of each gene to the total number of mutations was as follows: CRX, 2.8%; GUCY2D, 6.3%; and RPE65, 6.8%. No patients who harbored mutations in these genes had associated systemic abnormalities. Molecular diagnosis allowed definitive genetic counseling in a family affected with Best disease and LCA. Conclusions: Molecular diagnosis may be of benefit to patients affected with LCA. The relative paucity of mutations found in this study suggests that more LCAassociated genes remain to be discovered. Clinical Relevance: Molecular diagnosis can confirm and clarify the diagnosis of LCA. As genotype data accumulate, clinical phenotypes associated with specific mutations will be established. This will facilitate the counseling of patients on their visual prognosis and the likelihood of associated systemic anomalies.

Phenotype of three consanguineous Tunisian families with early-onset retinal degeneration caused by an R91W homozygous mutation in the RPE65 gene

“…RPE65 mutations are a common cause of EORD [14] and may be responsible in 6.1-11.4% of patients with mutations in homozygous or compound heterozygous form [9,26]. The disease-causing mutation mechanism of the missense mutation R91W…”

Progession of phenotype in Leber's congenital amaurosis with a mutation at the LCA5 locus

“…[12][13][14][15] In one genetic survey assessing the frequency of mutations in three known genes considered to have a major role in LCA, only 15.9% of the sample population harboured disease-causing mutations. 16 This implies a substantial proportion of cases with LCA result from mutations in as yet unidentified genes. This phenotypic variation seen in LCA is a consequence of this genetic heterogeneity.…”

Massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis

“…This patient is also a heterozygous carrier of c.472G>A (p.Ala158Thr) in CRX, which has previously been described in cone-rod dystrophy and LCA, as well as in 2/110 control individuals. 28,29 The presence of the A allele a single qPCR protocol enabled high-throughput amplification in a small volume, thereby overcoming the need for complex PCR multiplexing (Figure 1). 31 Moreover, qPCR enrichment provides an additional internal quality control.…”