Mutations in the CRB1 gene cause Leber congenital amaurosis

Objectives: To test the hypothesis that mutations in the CRB1 gene cause Le ber congenital amaurosis (LCA) and, if so, to describe the ocular phenotype of patients with LCA who harbor CRB1 sequence variations. Patients: One hundred ninety probands with a clinical diagnosis of LCA were selected from a cohort of 233 probands ascertained in 5 different countrie s. The remaining 43 probands (18%) were excluded because they harbored sequ ence variations in previously identified LCA genes. Methods: One hundred ninety unrelated individuals with LCA were screened fo r coding sequence mutations in the CRB1 gene with single-strand conformatio n polymorphism analysis followed by automated DNA sequencing. Results: Twenty-one of the 190 probands (9% of the total cohort of 233) and 2 (1.4%) of 140 controls harbored amino acid-altering sequence variations in the CRB1 gene (P=.003). Conclusions: in our cohort of patients with LCA, coding sequence variations were observed in the CRB1 gene more frequently than in any of the other 5 known LCA-associated genes. Likely disease-causing sequence variations have now been identified in 64 (28%) of 233 subjects in this cohort. Clinical Relevance: Molecular diagnosis can confirm and clarify the diagnos is in an increasing fraction of patients with LCA. As genotype data accumul ate, clinical phenotypes associated with specific mutations may be establis hed. This will facilitate the counseling of patients regarding their visual prognosis and the likelihood of associated systemic anomalies.