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E. Pomares, G. Marfany, R. Gonzàlez-Duarte; Rapid and Efficient SNP Genotyping for the Genetic Diagnosis of Autosomal Dominant and Recessive Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2008;49(13):6093. doi: https://doi.org/.
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Retinitis Pigmentosa (RP), the major cause for blindness in the adults, is an extremely heterogeneous monogenic disorder which shows all mendelian types of inheritance. Up to now, more than 30 RP genes have been described, 17 of which are involved in autosomal dominant (adRP) and 20 in autosomal recessive (arRP) forms. However, many cases remain unassigned. This high number of candidates (with no major gene neither mutation sites) makes conventional mutational screening time-consuming and costly for a small/medium sized laboratory. Nonetheless, this step is unavoidable for proper genetic diagnosis of patients and potential carriers, and it is a pre-requisite before approaching the identification of new RP genes and loci. The more is known about the genetic basis of this disease as well as other retinal distrophies, the more evidences are gathered in favor of allelic heterogeneity, that is, different mutations in the same gene cause clinically distinct diseases and are transmitted following different patterns of inheritance. Until now, 4 genes involved in autosomal dominant RP can -depending on the mutation- also cause autosomal recessive RP. In addition, 6 RP genes are responsible for some cases of Leber Congenital Amaurosis (LCA), increasing the complexity of the molecular diagnosis scenario.
Taking into account these data and our previous experience in the field, we have designed an innovative high-throughput time-cost effective strategy for cosegregation analysis of 39 RP and LCA genes by SNP genotyping on isolated families.
After a single and fast genotyping step, we have discarded the candidates that did not cosegregate with the disease and focused in the remaining genes. Subsequent mutational screening has allowed us to identify the causative mutations for several families.
This type of study is more powerful when the family is consanguineous in the arRP forms, and when more than 4 affected siblings are analyzed in the adRP forms. This approach can also be applied to other retinal diseases with high genetic heterogeneity.
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