@article {827, title = {Congenital Heart Defects Due to Missense Variants.}, journal = {Circ Genom Precis Med}, volume = {13}, year = {2020}, month = {2020 06}, pages = {e002843}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.119.002843}, author = {Morton, Sarah U and Agarwal, Radhika and Madden, Jill A and Genetti, Casie A and Brownstein, Catherine A and L{\'o}pez-Gir{\'a}ldez, Francesc and Choi, Jungmin and Seidman, Christine E and Seidman, Jonathan G and Lyon, Gholson J and Agrawal, Pankaj B} } @article {955, title = {De Novo Damaging Variants, Clinical Phenotypes, and Post-Operative Outcomes in Congenital Heart Disease.}, journal = {Circ Genom Precis Med}, volume = {13}, year = {2020}, month = {2020 08}, pages = {e002836}, abstract = {

BACKGROUND: De novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown.

METHODS: We studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease Genetic Network).

RESULTS: Two hundred ninety-four patients (11.7\%) had clinically significant de novo variants. Patients with de novo damaging variants were 2.4 times more likely to have extra-cardiac anomalies (=5.63{\texttimes}10). In 1268 patients (50.4\%) who had surgical data available and underwent open-heart surgery exclusive of heart transplantation as their first operation, we analyzed transplant-free survival following the first operation. Median follow-up was 2.65 years. De novo variants were associated with worse transplant-free survival (hazard ratio, 3.51; =5.33{\texttimes}10) and longer times to final extubation (hazard ratio, 0.74; =0.005). As de novo variants had a significant interaction with extra-cardiac anomalies for transplant-free survival (=0.003), de novo variants conveyed no additional risk for transplant-free survival for patients with these anomalies (adjusted hazard ratio, 1.96; =0.06). By contrast, de novo variants in patients without extra-cardiac anomalies were associated with worse transplant-free survival during follow-up (hazard ratio, 11.21; =1.61{\texttimes}10) than that of patients with no de novo variants. Using agnostic machine-learning algorithms, we identified de novo copy number variants at 15q25.2 and 15q11.2 as being associated with worse transplant-free survival and 15q25.2, 22q11.21, and 3p25.2 as being associated with prolonged time to final extubation.

CONCLUSIONS: In patients with congenital heart disease undergoing open-heart surgery, de novo variants were associated with worse transplant-free survival and longer times on the ventilator. De novo variants were most strongly associated with adverse outcomes among patients without extra-cardiac anomalies, suggesting a benefit for preoperative genetic testing even when genetic abnormalities are not suspected during routine clinical practice. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01196182.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.119.002836}, author = {Boskovski, Marko T and Homsy, Jason and Nathan, Meena and Sleeper, Lynn A and Morton, Sarah and Manheimer, Kathryn B and Tai, Angela and Gorham, Joshua and Lewis, Matthew and Swartz, Michael and Alfieris, George M and Bacha, Emile A and Karimi, Mohsen and Meyer, David and Nguyen, Khanh and Bernstein, Daniel and Romano-Adesman, Angela and Porter, George A and Goldmuntz, Elizabeth and Chung, Wendy K and Srivastava, Deepak and Kaltman, Jonathan R and Tristani-Firouzi, Martin and Lifton, Richard and Roberts, Amy E and Gaynor, J William and Gelb, Bruce D and Kim, Richard and Seidman, Jonathan G and Brueckner, Martina and Mayer, John E and Newburger, Jane W and Seidman, Christine E} } @article {953, title = {Systems Analysis Implicates WAVE2~Complex in the Pathogenesis of~Developmental Left-Sided Obstructive~Heart Defects.}, journal = {JACC Basic Transl Sci}, volume = {5}, year = {2020}, month = {2020 Apr}, pages = {376-386}, abstract = {

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins , , and and the regulators of small GTPase signaling and are critical to cardiac development.

}, issn = {2452-302X}, doi = {10.1016/j.jacbts.2020.01.012}, author = {Edwards, Jonathan J and Rouillard, Andrew D and Fernandez, Nicolas F and Wang, Zichen and Lachmann, Alexander and Shankaran, Sunita S and Bisgrove, Brent W and Demarest, Bradley and Turan, Nahid and Srivastava, Deepak and Bernstein, Daniel and Deanfield, John and Giardini, Alessandro and Porter, George and Kim, Richard and Roberts, Amy E and Newburger, Jane W and Goldmuntz, Elizabeth and Brueckner, Martina and Lifton, Richard P and Seidman, Christine E and Chung, Wendy K and Tristani-Firouzi, Martin and Yost, H Joseph and Ma{\textquoteright}ayan, Avi and Gelb, Bruce D} } @article {426, title = {Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Nov}, pages = {1593-1601}, abstract = {

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8\%, including a recessive founder mutation in GDF1 accounting for \~{}5\% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for \~{}11\% of Shone complex, and dominant FLT4 mutations accounting for 2.3\% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8\% of cases, including \~{}3\% of isolated CHD patients and \~{}28\% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70\% probability of being disease related. DNMs in \~{}440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

}, keywords = {Adult, Autistic Disorder, Cardiac Myosins, Case-Control Studies, Child, Exome, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Growth Differentiation Factor 1, Heart Defects, Congenital, Heterozygote, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Male, Mutation, Myosin Heavy Chains, Pedigree, Risk, Vascular Endothelial Growth Factor Receptor-3}, issn = {1546-1718}, doi = {10.1038/ng.3970}, author = {Jin, Sheng Chih and Homsy, Jason and Zaidi, Samir and Lu, Qiongshi and Morton, Sarah and DePalma, Steven R and Zeng, Xue and Qi, Hongjian and Chang, Weni and Sierant, Michael C and Hung, Wei-Chien and Haider, Shozeb and Zhang, Junhui and Knight, James and Bjornson, Robert D and Castaldi, Christopher and Tikhonoa, Irina R and Bilguvar, Kaya and Mane, Shrikant M and Sanders, Stephan J and Mital, Seema and Russell, Mark W and Gaynor, J William and Deanfield, John and Giardini, Alessandro and Porter, George A and Srivastava, Deepak and Lo, Cecelia W and Shen, Yufeng and Watkins, W Scott and Yandell, Mark and Yost, H Joseph and Tristani-Firouzi, Martin and Newburger, Jane W and Roberts, Amy E and Kim, Richard and Zhao, Hongyu and Kaltman, Jonathan R and Goldmuntz, Elizabeth and Chung, Wendy K and Seidman, Jonathan G and Gelb, Bruce D and Seidman, Christine E and Lifton, Richard P and Brueckner, Martina} } @article {302, title = {De novo mutations in histone-modifying genes in congenital heart disease.}, journal = {Nature}, volume = {498}, year = {2013}, month = {2013 Jun 13}, pages = {220-3}, abstract = {

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 {\textquoteright}poised{\textquoteright} 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.

}, keywords = {Adult, Case-Control Studies, Child, Chromatin, DNA Mutational Analysis, Enhancer Elements, Genetic, Exome, Female, Genes, Developmental, Heart Diseases, Histones, Humans, Lysine, Male, Methylation, Mutation, Odds Ratio, Promoter Regions, Genetic}, issn = {1476-4687}, doi = {10.1038/nature12141}, author = {Zaidi, Samir and Choi, Murim and Wakimoto, Hiroko and Ma, Lijiang and Jiang, Jianming and Overton, John D and Romano-Adesman, Angela and Bjornson, Robert D and Breitbart, Roger E and Brown, Kerry K and Carriero, Nicholas J and Cheung, Yee Him and Deanfield, John and DePalma, Steve and Fakhro, Khalid A and Glessner, Joseph and Hakonarson, Hakon and Italia, Michael J and Kaltman, Jonathan R and Kaski, Juan and Kim, Richard and Kline, Jennie K and Lee, Teresa and Leipzig, Jeremy and Lopez, Alexander and Mane, Shrikant M and Mitchell, Laura E and Newburger, Jane W and Parfenov, Michael and Pe{\textquoteright}er, Itsik and Porter, George and Roberts, Amy E and Sachidanandam, Ravi and Sanders, Stephan J and Seiden, Howard S and State, Mathew W and Subramanian, Sailakshmi and Tikhonova, Irina R and Wang, Wei and Warburton, Dorothy and White, Peter S and Williams, Ismee A and Zhao, Hongyu and Seidman, Jonathan G and Brueckner, Martina and Chung, Wendy K and Gelb, Bruce D and Goldmuntz, Elizabeth and Seidman, Christine E and Lifton, Richard P} }