Clinical genetics
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Array comparative genomic hybridization (array CGH) is now widely adopted as a first-tier clinical diagnostic test in individuals with unexplained developmental delay/intellectual disability (DD/ID) and congenital anomalies. Our study aimed at enlarging the phenotypic spectrum associated with clinically relevant copy number variants (CNVs) as well as delineating clinical criteria, which may help separating patients with pathogenic CNVs from those without pathogenic CNVs. We performed a retrospective review of clinical and array CGH data of 342 children with unexplained DD/ID. ⋯ Array CGH detected pathogenic CNVs in 13.2% of the patients. Congenital anomalies, especially heart defects, as well as primary microcephaly, short stature and failure to thrive were clearly more frequent in children with pathogenic CNVs compared with children with normal array CGH results. Thus, we assume that in patients with unexplained DD/ID, array CGH will more probably detect a significant CNV if any of these features is part of the patient's phenotype.
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We have utilized a novel application of human genetics, illuminating the important role that rare genetic disorders can play in the development of novel drugs that may be of relevance for the treatment of both rare and common diseases. By studying a very rare Mendelian disorder of absent pain perception, congenital indifference to pain, we have defined Nav1.7 (endocded by SCN9A) as a critical and novel target for analgesic development. Strong human validation has emerged with SCN9A gain-of-function mutations causing inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder, both Mendelian disorder of spontaneous or easily evoked pain. ⋯ On the basis of this, we have developed a novel compound (XEN402) that exhibits potent, voltage-dependent block of Nav1.7. In a small pilot study, we showed that XEN402 blocks Nav1.7 mediated pain associated with IEM thereby demonstrating the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof-of-concept. Our approach underscores the critical role that human genetics can play by illuminating novel and critical pathways pertinent for drug discovery.
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Twin studies provide a method for estimating the heritability of phenotypes and for examining genetic and environmental relationships between phenotypes. We conducted a systematic review of twin studies of pain, including both clinical and experimental pain phenotypes. Fifty-six papers were included, whereof 52 addressed clinical phenotypes. ⋯ Whereas there is evidence for substantial common genetic risk across many clinical pain conditions, different experimental pain phenotypes appear to be associated with different genetic factors. Recommendations for future research include inclusion of pain intensity scaling and number of pain sites in phenotyping. Furthermore, studies examining the genetic relationships between pain phenotypes, in particular between clinical and experimental phenotypes, should be prioritized.
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There are now several strong opioids available to choose from for the relief of moderate to severe pain. On a population level, there is no difference in terms of analgesic efficacy or adverse reactions between these drugs; however, on an individual level there is marked variation in response to a given opioid. ⋯ If personalized prescribing could be achieved this would have a major impact at an individual level to facilitate safe, effective and rapid symptom control. This review presents some of the recent positive advances in opioid pharmacogenetic studies, focusing on associations between candidate genes and the three main elements of opioid response: analgesic, upper gastrointestinal and central adverse reactions.