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I. H. Maumenee, N. J. Izquierdo, V. M. Villegas, R. K. Koenekoop; Leber Congenital Amaurosis (LCA) on Puerto Rico and the Virgin Islands: A Genetic Study. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2580.
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© ARVO (1962-2015); The Authors (2016-present)
To ascertain the patients with LCA on Puerto Rico and the Virgin Islands (population: 4.5 million), to search for new genes and/or mutations and to elucidate genotype/phenotype correlations.
We ascertained 15 pedigrees with LCA. An ocular evaluation was obtained on all patients including best corrected visual acuity, anterior segment slit lamp evaluation, fundus examination, OCT and ERG. Blood samples were obtained for DNA analysis after informed consent. APEX technology was used to screen for known mutations (Asper Ophthalmics, Version, 2008). Screen-negative patients underwent SNP genotyping using Illumina Ultra High-Throughput Bead Lab Technology to identify homozygous regions. They were probed for candidate genes. Candidate genes underwent automated sequencing.
After pedigree construction, we retained 13, eight of which contained parental consanguinity. Causative mutations were identified in 11. The identified mutations included: AIPL1 G163X; CRB1 c611-617del; CRB1 C480R; GUCY2D S448X; RPGRIP1 D1114G; LCA5 R48X; SPATA7 M140RfsX10 and NPHP5 R461X. In six pedigrees we observed homozygous or compound heterozygous mutations in CRB1. SNP analysis in two pedigrees showed homozygous regions encompassing the LCA5 and SPATA7 loci respectively. Sequencing identified two novel mutations: hmz LCA5 p.R48X and hmz SPATA7 p.M140RfsX10. One patient was heterozygous for GUCY2D S448X and RPGRIP1 D1114G; these mutations were thought to not adequately explain the disease. In one patient only a heterozygous CRB1 mutation was identified. The phenotype of CRB1 mutations was characterized by Coats disease in half of the patients. A patient with GUCY2D S448X had a stable visual acuity of 20/200, a benign phenotype for mutations in GUCY2D. Places of origin for common ancestral couples could be mapped.
Mutations in seven of the 15 known LCA genes were identified on Puerto Rico and the Virgin Islands. Two hmz mutations were novel (LCA5 p.R48X; SPATA7 p.M140RfsX10). In two LCA patients the phenotype remained unexplained. When screening patients for the mutations identified in the population, at least one secondary mutation was found in all affected. Consanguinity was found in eight out of 13 pedigrees; common ancestral communities could be identified for patients with identical mutations. It is possible to screen the population for carriers at risk of transmitting the disease.
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