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Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC).(More)
The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of(More)
PURPOSE The accurate interpretation of variation in Mendelian disease genes has lagged behind data generation as sequencing has become increasingly accessible. Ongoing large sequencing efforts present huge interpretive challenges, but they also provide an invaluable opportunity to characterize the spectrum and importance of rare variation. METHODS We(More)
BACKGROUND Four- or five-option multiple choice questions (MCQs) are the standard in health-science disciplines, both on certification-level examinations and on in-house developed tests. Previous research has shown, however, that few MCQs have three or four functioning distractors. The purpose of this study was to investigate non-functioning distractors in(More)
Spontaneously arising (de novo) genetic variants are important in human disease, yet every individual carries many such variants, with a median of 1 de novo variant affecting the protein-coding portion of the genome. A recently described mutational model provides a powerful framework for the robust statistical evaluation of such coding variants, enabling(More)
Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics(More)
Next-generation sequencing (NGS) provides an unprecedented opportunity to assess genetic variation underlying human disease. Here, we compared two NGS approaches for diagnostic sequencing in inherited arrhythmia syndromes. We compared PCR-based target enrichment and long-read sequencing (PCR-LR) with in-solution hybridization-based enrichment and short-read(More)
Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These(More)
CONTEXT Multiple-choice questions (MCQs) are frequently used to assess students in health science disciplines. However, few educators have formal instruction in writing MCQs and MCQ items often have item-writing flaws. The purpose of this study was to examine the impact of item-writing flaws on student achievement in high-stakes assessments in a nursing(More)
The fast moving field of genomic medicine is already impacting on clinical care and cardiologists are fortunate to be in a position to benefit early from the transformative advances in genomics. However, the challenges associated with genomics in the clinic in general, and with next generation sequencing technologies in particular, are significant and(More)