De novo mutations in histone modifying genes in congenital heart disease

By Samir Zaidi, Murim Choi, H. Wakimoto, Lijiang Ma, Jianming Jiang, J. Overton, Angela Romano-Adesman, R. Bjornson, R. Breitbart, Kerry K. Brown and 40 more. Nature, 2013

900 citations recorded by the source corpus.

Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent–offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left–right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes ‘poised’ promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.

Subfields: Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b9fa8eb229c8a5400a4468b69bc23ef4836ffcc6

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In Molecular Biology

Citations in the corpus

The Next-Generation Sequencing Revolution and Its Impact on Genomics (2013, positive): “Similar WES approaches have implicated genes expressed in the developing heart for sporadic congenital heart disease (Zaidi et al., 2013) and genes encoding chromatin regulators for sporadic ALS (Chesi et al., 2013).”
De novo mutations in Congenital Heart Disease with Neurodevelopmental and Other Birth Defects (2015, positive): “(A) The enrichment (ratio of observed to expected) of damaging de novo mutations in HHE genes is shown for each phenotype (±95% confidence interval).”
Comprehensive Analysis of Tissue-wide Gene Expression and Phenotype Data Reveals Tissues Affected in Rare Genetic Disorders (2017, background): “As such, prioritizing de novo mutation candidates in patients with congenital heart diseases based on expression levels in the heart successfully distinguished cases from controls (Zaidi et al., 2013).”
Prevalence and architecture of de novo mutations in developmental disorders (2017, positive): “We combined this analysis with 4,224 published DNMs in 3,287 affected individuals from thirteen exome-or genome-sequencing studies 3–14 (Supplementary Table 2) that exhibited a similar excess of DNMs as our curated set of DD-associated genes (Extended Data Fig.”