@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 {445, title = {The Congenital Heart Disease Genetic Network Study: Cohort description.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0191319}, abstract = {

The Pediatric Cardiac Genomics Consortium (PCGC) designed the Congenital Heart Disease Genetic Network Study to provide phenotype and genotype data for a large congenital heart defects (CHDs) cohort. This article describes the PCGC cohort, overall and by major types of CHDs (e.g., conotruncal defects) and subtypes of conotrucal heart defects (e.g., tetralogy of Fallot) and left ventricular outflow tract obstructions (e.g., hypoplastic left heart syndrome). Cases with CHDs were recruited through ten sites, 2010-2014. Information on cases (N = 9,727) and their parents was collected through interviews and medical record abstraction. Four case characteristics, eleven parental characteristics, and thirteen parent-reported neurodevelopment outcomes were summarized using counts and frequencies and compared across CHD types and subtypes. Eleven percent of cases had a genetic diagnosis. Among cases without a genetic diagnosis, the majority had conotruncal heart defects (40\%) or left ventricular outflow tract obstruction (21\%). Across CHD types, there were significant differences (p<0.05) in the distribution of all four case characteristics (e.g., sex), four parental characteristics (e.g., maternal pregestational diabetes), and five neurodevelopmental outcomes (e.g., learning disabilities). Several characteristics (e.g., sex) were also significantly different across CHD subtypes. The PCGC cohort is one of the largest CHD cohorts available for the study of genetic determinants of risk and outcomes. The majority of cases do not have a genetic diagnosis. This description of the PCGC cohort, including differences across CHD types and subtypes, provides a reference work for investigators who are interested in collaborating with or using publically available resources from the PCGC.

}, keywords = {Adult, Cohort Studies, Female, Gene Regulatory Networks, Heart Defects, Congenital, Humans, Male, Phenotype}, issn = {1932-6203}, doi = {10.1371/journal.pone.0191319}, author = {Hoang, Thanh T and Goldmuntz, Elizabeth and Roberts, Amy E and Chung, Wendy K and Kline, Jennie K and Deanfield, John E and Giardini, Alessandro and Aleman, Adolfo and Gelb, Bruce D and Mac Neal, Meghan and Porter, George A and Kim, Richard and Brueckner, Martina and Lifton, Richard P and Edman, Sharon and Woyciechowski, Stacy and Mitchell, Laura E and Agopian, A J} } @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} }