51. Combining gene mapping and phenotype assessment for fast mutation finding in non consanguineous autosomal recessive retinitis pigmentosa
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Hébrard, Maxime, Bocquet, Béatrice, Meunier, Isabelle, Coustes-Chazalette, Delphine, Hérald, Emilie, Sénéchal, Audrey, Bolland Augé, Anne, Zelenika, Diana, Manès, Gaël, Hamel, Christian P, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Centre National de Génotypage (CNG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
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non consanguineous families ,retinitis pigmentosa ,phenotype characterization ,autosomal recessive inheritance ,gene mapping - Abstract
International audience; Among inherited retinal dystrophies, autosomal recessive retinitis pigmentosa (arRP) is the most genetically heterogenous condition with 32 genes currently known that account for ~60 % of patients. Molecular diagnosis thus requires the tedious systematic sequencing of 506 exons. To rapidly identify the causative mutations, we devised a strategy that combines gene mapping and phenotype assessment in small non consanguineous families. Two unrelated sibships with arRP had whole-genome scan using SNP microchips. Chromosomal regions were selected by calculating a score based on SNP coverage and genotype identity of affected patients. Candidate genes from the regions with the highest scores were then selected based on phenotype concordance of affected patients with previously described phenotype for each candidate gene. For families RP127 and RP1459, 33 and 40 chromosomal regions showed possible linkage, respectively. By comparing the scores with the phenotypes, we ended with one best candidate gene for each family, namely TULP1 and C2ORF71 for RP127 and RP1459, respectively. We found that RP127 patients were compound heterozygous for 2 novel TULP1 mutations, p.Arg311Gln and p.Arg342Gln, and that RP1459 patients were compound heterozygous for 2 novel C2ORF71 mutations, p.Leu777PhefsX34 and p.Leu777AsnfsX28. Phenotype assessment showed that TULP1 patients had severe early onset arRP and that C2ORF71 patients had a cone rod dystrophy type of arRP. Only 2 affected individuals in each sibship were sufficient to lead to mutation identification by screening the best candidate gene selected by a combination of gene mapping and phenotype characterization.
- Published
- 2011
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