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A.J. Lotery, S.G. Jacobson, R.G. Weleber, A. Iannaccone, P. Namperumalsamy, G.A. Fishman, A. Levin, B.L. Lam, E. Heon, E.M. Stone; Prevalence of Mutations in the RPE65, CRX, AIPL1, TULP1, GUCY2D and CRB1 Genes in Leber Congenital Amaurosis . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2301.
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Purpose:To identify the prevalence of mutations in the RPE65, CRX, AIPL1, TULP1, GUCY2D and CRB1 genes in a large cohort of Leber Congenital Amaurosis (LCA) patients and to ascertain genotype-phenotype correlations. Methods: 299 patients with LCA were genotyped by single strand conformation polymorphism electrophoresis and direct sequencing in six genes known to be mutated in LCA. Clinical correlations were ascertained in patients for whom sequence variations were established. 176 patients had previously been genotyped on the CRX, GUCY2D and RPE65 genes. Results: 98 sequence variants were found in 102 probands (34 %). The prevalence of sequence changes for each gene were: TULP1 (0%), CRX (2%), AIPL1 (5 %), RPE65 (8%), GUCY2D (9 %) and CRB1 (10 %). One patient had a non-conservative change in RPE65 and two non-conservative changes in GUCY2D. Clinical data were available on 66 patients with sequence variations in all genes except TULP1. Clinically, 87 % of patients were hyperopic with no significant difference in refractions between genetic groups tested. Visual acuities ranged from 20/30 to light perception. Photophobia was observed with CRB1 and GUCY2D, nyctalopia with RPE65, GUCY2D, CRB1 and AIPL1 and nystagmus with AIPL1, CRB1, CRX, GUCY2D and RPE65 sequence variations. Three patients with sequence changes in GUCY2D were also noted to have either developmental delay (2) or mental retardation (1). There were no reports of renal dysfunction in this cohort. Conclusions:The molecular cause of LCA can now be determined in one third of patients with this clinical diagnosis. Ocular phenotype is similar with these various genotypes. Systemic associations that can complicate LCA were not a common feature of any of the genotypes. Developmental delay or mental retardation, however, was seen but only in three patients with GUCY2D mutations.
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