Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.

Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD

Challenging the New Orthodoxy: A Critique of SPLISS and Variable-Oriented Approaches to Comparing Sporting Nations

Research Question: In recent years the comparative sport policy field has become dominated by the ‘SPLISS’ approach developed by De Bosscher and colleagues. While this approach has developed important insights into the statistical relationship between key groups of independent variables and indicators of elite sport policy success, nevertheless its attempts to identify and explain both statistical association and causal relationships have significant limitations.The paper thus seeks to address the question of the nature of such strengths and limitations and their implications for theory, policy and practice. Methods: As a review paper it develops a critical evaluation of claims made for the SPLISS approach to variable oriented comparative policy analysis. Results: The paper identifies and focuses on the implications of six key problems for the SPLISS approach, namely: philosophical assumptions and causal variables; the black box problem; internal validity issues; non-equivalence and reliability; the neglect of agency; and misconceptions in the use of mixed methods. Implications: The paper’s findings represent a challenge to the hegemony of this variable-oriented approach and they argue not for replacement or rejection of such an approach, but for recognition of its limitations, and of the opportunities for complementing it with case-driven, qualitative analysis generating causal accounts of policy outcome