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.

Action research and reflective practice: towards a holistic view

Two concepts that have captured the imagination of the educational community in the last 60 years have been those of ‘reflective practice’ and ‘action research’. Both, in their various forms, are considered to be critical dimensions of the professional development of teachers. However, whilst both were receiving academic attention during the 1930s and 1940s (Lewin, 1934, cited in Adelman, 1993; Lewin, 1946; Dewey, 1933), it was not until Stenhouse’s (1975) notion of the teacher-as-researcher that the two came most compellingly into relationship and educational action research as a process, which held at its centre different kinds of reflection, began to be reformulated in Britain (Carr, 1993). This article considers the important part played in teachers’ development by different kinds of action research. Its central thesis is that, although action research has a critical role to play not least as a means of building the capacity of teachers as researchers of their own practice, there has been insufficient attention given to both the nature of reflection in the action research process, and its relationship to the purposes, processes and outcomes. The article challenges the rational, cognitive models of reflection that are implicit in much of the action research literature. It suggests that more attention needs to be given to the importance of the role of emotion in understanding and developing the capacities for reflection which facilitates personal, professional and ultimately system change.