title: Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis.
abstract: 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 genotyping is, however, required to establish genetically defined subgroups of patients ready for therapy. Here, we report a comprehensive mutational analysis of the all known genes in 179 unrelated LCA patients, including 52 familial and 127 sporadic (27/127 consanguineous) cases. 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%). The clinical history of all patients with mutations was carefully revisited to search for phenotype variations. Sound genotype-phenotype correlations were found that allowed us 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 us 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. These flowcharts will hopefully lighten the heavy task of genotyping new patients but only if one has access to the most precise clinical history since birth.
authors.affiliation: Unité de Recherches sur les Handicaps Génétiques de l'Enfant, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Hanein
authors.forename: Isabelle
authors.initials: I
authors.lastname: Perrault
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gerber
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Tanguy
authors.forename: Fabienne
authors.initials: F
authors.lastname: Barbet
authors.forename: Dominique
authors.initials: D
authors.lastname: Ducroq
authors.forename: Patrick
authors.initials: P
authors.lastname: Calvas
authors.forename: Hélène
authors.initials: H
authors.lastname: Dollfus
authors.forename: Christian
authors.initials: C
authors.lastname: Hamel
authors.forename: Tuija
authors.initials: T
authors.lastname: Lopponen
authors.forename: Francis
authors.initials: F
authors.lastname: Munier
authors.forename: Louisa
authors.initials: L
authors.lastname: Santos
authors.forename: Stavit
authors.initials: S
authors.lastname: Shalev
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Zafeiriou
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Dufier
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rozet
authors.forename: Josseline
authors.initials: J
authors.lastname: Kaplan
mesh_terms: D001766:Blindness / Q000151:congenital / Q000175:diagnosis* / Q000235:genetics; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D012162:Retinal Degeneration / Q000235:genetics*; D009626:Terminology as Topic; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C448939:CRB1 protein, human; C415903:RPGRIP1 protein, human; C105443:TULP1 protein, human