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A. I. Den Hollander, I. Lopez, S. Yzer, K. W. Littink, M. A. Musarella, G. A. Fishman, I. H. Maumenee, K. Rohrschneider, F. P. M. Cremers, R. K. Koenekoop; Identification of Novel Mutations in Patients With Leber Congenital Amaurosis by Genome-Wide Homozygosity Mapping With SNP Microarrays. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2332.
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Leber congenital amaurosis (LCA) represents a group of severe retinal dystrophies, causing visual impairment during the first months of life. Juvenile retinitis pigmentosa (RP) is considered milder, but has significant overlap with LCA. Thus far, mutations in 11 genes have been associated with autosomal recessive LCA and juvenile RP. The purpose of this study was to use homozygosity mapping to identify mutations in known LCA and juvenile RP genes, and to identify novel genes for LCA and juvenile RP.
The genomes of 93 consanguineous and non-consanguineous patients with LCA and juvenile RP were analyzed for homozygous chromosomal regions using genome-wide SNP microarrays. In most patients all known mutations in the known genes were previously excluded with the LCA mutation chip. Known LCA and juvenile RP genes residing in the identified homozygous regions were further analyzed by sequencing.
Significant homozygous regions were detected in 26 (84%) of 31 consanguineous patients, and in 33 (53%) of 62 non-consanguineous patients. Homozygous mutations in the CRB1, LRAT, RPE65 and TULP1 genes were identified in 12 patients, including 8 novel mutations. Eight patients were from consanguineous marriages, but in 4 patients no consanguinity was reported. In 10 of the 12 patients the causative mutation was present in the largest or second largest homozygous segment of the patient's genome.
Homozygosity mapping using SNP microarrays identified mutations in a significant proportion (30%) of consanguineous LCA and juvenile RP patients, and in a small number (6%) of non-consanguineous patients. One small LCA family with 4 affected sibs that was included in this study was instrumental to recently identify the CEP290 gene as one of the most frequently mutated LCA genes. Significant homozygous regions were detected in 35 patients, which did not map to known LCA or juvenile RP genes, and may be instrumental to identify additional novel LCA or juvenile RP genes.
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