Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data

To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following in silico triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with UCHL1 , and independent confirmatory evidence has recently been published for four more. We highlight a further seven compelling associations: hypertrophic cardiomyopathy with DYSF and SLC4A3 where both genes show high/specific heart expression and existing associations to skeletal dystrophies or short QT syndrome respectively; monogenic diabetes with UNC13A with a known role in the regulation of β cells and a mouse model with impaired glucose tolerance; epilepsy with KCNQ1 where a mouse model shows seizures and the existing long QT syndrome association may be linked; early onset Parkinson's disease with RYR1 with existing links to tremor pathophysiology and a mouse model with neurological phenotypes; anterior segment ocular abnormalities associated with POMK showing expression in corneal cells and with a zebrafish model with developmental ocular abnormalities; and cystic kidney disease with COL4A3 showing high renal expression and prior evidence for a digenic or modifying role in renal disease. Confirmation of all 88 associations would lead to potential diagnoses in 456 molecularly undiagnosed cases within the 100KGP, as well as other rare disease patients worldwide, highlighting the clinical impact of a large-scale statistical approach to rare disease gene discovery

Factor V Leiden, estrogen, and multimorbidity association with venous thromboembolism in a British-South Asian cohort

Summary: Multimorbidity, estrogen use, and Factor V Leiden (FVL) are known independent risk factors for venous thromboembolism (VTE). This cross-sectional analysis of women in the Genes & Health British-South Asian cohort (N 20,048) linked the F5 SNP rs6025 with estrogen prescribing data and VTE events. Multivariable logistic regression was used to test the association between estrogen use, FVL, common medical co-morbidities, and VTE. Estrogens were prescribed to 30% of women. 3% of participants were FVL carriers. 439 participants had a VTE event (2.2%), and VTE prevalence increased with obesity, hypertension, dyslipidemia, chronic kidney disease, estrogen use, and in the presence of FVL. One medical condition above was independently associated with VTE with an OR 1.6 (CI 1.2–2.0, p 0.001); two medical conditions OR 2.7 (CI 2.0–3.7, p < 0.001); three OR 5.3 (CI 3.8–7.4, p < 0.001); four OR 8.1 (CI 4.9–13.0, p < 0.001). Multimorbidity and FVL compound risk of VTE with estrogen use

Ethical considerations for genetic testing in the context of mandated cardiac screening before athletic participation

status: publishe

UK Prescribing Safety Assessment (PSA):The development, implementation and outcomes of a national online prescribing assessment

AIMS: The United Kingdom (UK) Prescribing Safety Assessment (PSA) is a 2-h online assessment of basic competence to prescribe and supervise the use of medicines. It has been undertaken by students and doctors in UK medical and foundation schools for the past decade. This study describes the academic characteristics and performance of the assessment; longitudinal performance of candidates and schools; stakeholder feedback; and surrogate markers of prescribing safety in UK healthcare practice.METHODS: We reviewed the performance data generated by over 70 000 medical students and 3700 foundation doctors who have participated in the PSA since its inception in 2013. These data were supplemented by Likert scale and free text feedback from candidates and a variety of stakeholder groups. Further data on medication incidents, collected by national reporting systems and the regulatory body, are reported, with permission.RESULTS: We demonstrate the feasibility, high quality and reliability of an online prescribing assessment, uniquely providing a measure of prescribing competence against a national standard. Over 90% of candidates pass the PSA on their first attempt, while a minority are identified for further training and assessment. The pass rate shows some variation between different institutions and between undergraduate and foundation cohorts. Most responders to a national survey agreed that the PSA is a useful instrument for assessing prescribing competence, and an independent review has recommended adding the PSA to the Medical Licensing Assessment. Surrogate markers suggest there has been improvement in prescribing safety in practice, temporally associated with the introduction of the PSA but other factors could be influential too.CONCLUSIONS: The PSA is a practical and cost-effective way of delivering a reliable national assessment of prescribing competence that has educational impact and is supported by the majority of stakeholders. There is a need to develop national systems to identify and report prescribing errors and the harm they cause, enabling the impact of educational interventions to be measured.</p