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

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.

A Diagnostic System Using Broad Categories With Clinicaly Relevant Specifiers: Lessons for ICD-10

A diagnostic system for ICD-11 is proposed which commences with broad reorganization and simplification of the current categories and the use of clinically relevant specifiers. Such changes have implications for the positioning of diagnostic groups and lead to a range of possibilities for improving terminology and the juxtaposition of individual conditions. The development of ICD-11 provides the first opportunity in almost two decades to improve the validity and reliability of the international classification system. Widespread change in broad categories and criteria cannot be justified by research that has emerged since the last revision. It would also be disruptive to clinical practice and might devalue past research work. However, the case for reorganization of the categories is stronger and has recently been made by an eminent international group of researchers (Andrews et al., 2009). A simpler, interlinked diagnostic system is proposed here which is likely to have fewer categories than its predecessor. There are major advantages of such a system for clinical practice and research and it could also produce much needed simplification for primary care (Gask et al., 2008) and the developing world (Wig, 1990; Kohn et al., 2004).

Recovering Social Networks from Individual Attributes

One of the most important challenges of network analysis remains the scarcity of reliable information on existing connection structures. This work explores theoretical and empirical methods of inferring directed networks from nodes attributes and from functions of these attributes that are computed for connected nodes. We discuss the conditions, under which an underlying connection structure can be (probabilistically) recovered, and propose a Bayesian recovery algorithm. In an empirical application, we test the algorithm on the data from the European School Survey Project on Alcohol and Other Drugs.

Non-uptake of predictive genetic testing for BRCA1/2 among relatives of known carriers: Attributes, cancer worry, and barriers to testing in a multicenter clinical cohort

BRCA1/2 test decliners/deferrers have received almost no attention in the literature and this is the first study of this population in the United Kingdom. The aim of this multicenter study is to examine the attributes of a group of individuals offered predictive genetic testing for breast/ovarian cancer predisposition who did not wish to proceed with testing at the time of entry into this study. This forms part of a larger study involving 9 U.K. centers investigating the psychosocial impact of predictive genetic testing for BRCA1/2. Cancer worry and reasons for declining or deferring BRCA1/2 predictive genetic testing were evaluated by questionnaire following genetic counseling. A total of 34 individuals declined the offer of predictive genetic testing. Compared to the national cohort of test acceptors, test decliners are significantly younger. Female test decliners have lower levels of cancer worry than female test acceptors. Barriers to testing include apprehension about the result, traveling to the genetics clinic, and taking time away from work/family. Women are more likely than men to worry about receiving less screening if found not to be a carrier. The findings do not indicate that healthy BRCA1/2 test decliners are a more vulnerable group in terms of cancer worry. However, barriers to testing need to be discussed in genetic counseling.