Development of a Diagnostic Genetic Test for Simplex and Autosomal Recessive Retinitis Pigmentosa


Autoria(s): Clark, G.R.; Crowe, Paul; Muszynska, Dorota; O'Prey, Dominic; O'Neill, J.; Alexander, S.; Willoughby, Colin; McKay, Gareth; Silvestri, Giuliana; Simpson, David
Data(s)

01/11/2010

Resumo

PURPOSE: Retinitis pigmentosa (RP) causes hereditary blindness in adults (prevalence, approximately 1 in 4000). Each of the more than 30 causative genes identified to date are responsible for only a small percentage of cases. Genetic diagnosis via traditional methods is problematic, and a single test with a higher probability of detecting the causative mutation would be very beneficial for the clinician. The goal of this study therefore was to develop a high-throughput screen capable of detecting both known mutations and novel mutations within all genes implicated in autosomal recessive or simplex RP. DESIGN: Evaluation of diagnostic technology. PARTICIPANTS AND CONTROLS: Participants were 56 simplex and autosomal recessive RP patients, with 360 population controls unscreened for ophthalmic disease. METHODS: A custom genechip capable of resequencing all exons containing known mutations in 19 disease-associated genes was developed (RP genechip). A second, commercially available arrayed primer extension (APEX) system was used to screen 501 individual previously reported variants. The ability of these high-throughput approaches to identify pathogenic variants was assessed in a cohort of simplex and autosomal recessive RP patients. MAIN OUTCOME MEASURES: Number of mutations and potentially pathogenic variants identified. RESULTS: The RP genechip identified 44 sequence variants: 5 previously reported mutations; 22 known single nucleotide polymorphisms (SNPs); 11 novel, potentially pathogenic variants; and 6 novel SNPs. There was strong concordance with the APEX array, but only the RP genechip detected novel variants. For example, identification of a novel mutation in CRB1 revealed a patient, who also had a single previously known CRB1 mutation, to be a compound heterozygote. In some individuals, potentially pathogenic variants were discovered in more than one gene, consistent with the existence of disease modifier effects resulting from mutations at a second locus. CONCLUSIONS: The RP genechip provides the significant advantage of detecting novel variants and could be expected to detect at least one pathogenic variant in more than 50% of patients. The APEX array provides a reliable method to detect known pathogenic variants in autosomal recessive RP and simplex RP patients and is commercially available. High-throughput genotyping for RP is evolving into a clinically useful genetic diagnostic tool.

Identificador

http://pure.qub.ac.uk/portal/en/publications/development-of-a-diagnostic-genetic-test-for-simplex-and-autosomal-recessive-retinitis-pigmentosa(9dadc51c-10cb-4210-89bc-d10256bbea59).html

http://dx.doi.org/10.1016/j.ophtha.2010.02.029

http://www.scopus.com/inward/record.url?scp=78049241409&partnerID=8YFLogxK

Idioma(s)

eng

Direitos

info:eu-repo/semantics/restrictedAccess

Fonte

Clark , G R , Crowe , P , Muszynska , D , O'Prey , D , O'Neill , J , Alexander , S , Willoughby , C , McKay , G , Silvestri , G & Simpson , D 2010 , ' Development of a Diagnostic Genetic Test for Simplex and Autosomal Recessive Retinitis Pigmentosa ' Ophthalmology , vol 117 , no. 11 , pp. 2169-2177 . DOI: 10.1016/j.ophtha.2010.02.029

Palavras-Chave #/dk/atira/pure/subjectarea/asjc/2700/2731 #Ophthalmology
Tipo

article