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Novel high‐throughput SNP genotyping cosegregation analysis for genetic diagnosis of autosomal recessive retinitis pigmentosa and Leber congenital amaurosis
Author(s) -
Pomares Esther,
Marfany Gemma,
Brión Ma José,
Carracedo Angel,
GonzàlezDuarte Roser
Publication year - 2007
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20479
Subject(s) - retinitis pigmentosa , genetics , biology , disease gene identification , genotyping , candidate gene , genetic linkage , genetic heterogeneity , snp array , gene , snp genotyping , pedigree chart , snp , mutation , single nucleotide polymorphism , phenotype , genotype , exome sequencing
Abstract Retinitis pigmentosa (RP), the major cause of blindness in adults, is an extremely heterogeneous monogenic disorder. More than 32 causative genes have been identified, 18 of which are involved in autosomal recessive RP (arRP); however, more than 50% of the cases remain unassigned. There are no major causative genes identified for arRP nor any prevalent mutations, which make mutational screening of the already reported RP genes extremely time consuming and costly. Nonetheless, this step is unavoidable for genetic diagnosis of patients and potential carriers, and it is a prerequisite before approaching the identification of new RP genes and loci. We have designed an innovative high‐throughput time‐ and cost‐effective strategy for cosegregation analysis of 22 genes of arRP and Leber congenital amaurosis (LCA; an autosomal recessive retinal dystrophy that shares some of the RP genes and traits) by SNP genotyping. This novel indirect method has been validated in a panel of 54 consanguineous and nonconsanguineous arRP families. In a single and fast genotyping step: 1) we discarded all the 22 candidate genes in 13% of the pedigrees, highlighting the families of choice to search for novel arRP genes/loci; 2) we excluded an average of 18–19 genes per family, thus diminishing the number of genes to screen for pathogenic mutations; and 3) we identified CERKL as the causative RP gene in a family in which this candidate had been previously discarded by microsatellite cosegregation analysis. This type of approach can also be applied to other nonretinal diseases with high genetic heterogeneity, such as hereditary deafness or Parkinson disease. Hum Mutat 28(5), 511–516, 2007. © 2007 Wiley‐Liss, Inc.