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S. Hanein, I. Perrault, S. Gerber, G. Tanguy, J.–M. Rozet, J. Kaplan; LEBER CONGENITAL AMAUROSIS: COMPREHENSIVE SURVEY OF THE GENETIC HETEROGENEITY, REFINEMENT OF THE CLINICAL DEFINITION AND PHENOTYPE–GENOTYPE CORRELATIONS AS A STRATEGY FOR MOLECULAR DIAGNOSIS. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4729.
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Purpose: Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies, responsible for congenital blindness. Disease–associated mutations have been hitherto reported in seven genes. These genes are all expressed preferentially in the photoreceptor cells or the retinal pigment epithelium but they are involved in strikingly different physiologic pathways resulting in an unforeseeable physiopathologic variety. This wide genetic and physiologic heterogeneity that could largely increase in the coming years, hinders the molecular diagnosis in LCA patients. The aim of the present work was to establish phenotype–genotype correlations as a pre–requisite to genotyping of patients affected with LCA. Methods: A comprehensive mutational analysis of the all known genes was performed using DHPLC and direct sequencing in 179 unrelated LCA patients, including 52 familial and 127 sporadic (27/127 consanguineous) cases. To establish phenotype–genotype correlations, the clinical history of all patients with mutations was carefully revisited in search for phenotype variations. Results: Mutations were identified in 47.5% patients. GUCY2D appeared to account for most LCA cases of our series (21.2%), followed by CRB1 (10%), RPE65 (6.1%), RPGRIP1 (4.5%), AIPL1 (3.4%), TULP1 (1,7%) and CRX (0.6%). Sound genotype–phenotype correlations were found that allowed to divide patients into two main groups. The first one includes patients whose symptoms fit the traditional definition of LCA i.e. congenital or very early cone–rod dystrophy, while the second group gathers patients affected with severe yet progressive rod–cone dystrophy. Besides objective ophthalmologic data allowed to subdivide each group into two subtypes. Based on these findings, we have drawn decisional flowcharts directing the molecular analysis of LCA genes in a given case. Conclusions: This work which lightens henceforward the heavy task of large scale genotyping in LCA and makes possible to establish genetically defined subgroups of patients ready for therapy.
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