@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 {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 {543, title = {Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 Feb 01}, pages = {309-320}, abstract = {

Exome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in~vitro, and in~vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.12.015}, author = {Martinelli, Simone and Krumbach, Oliver H F and Pantaleoni, Francesca and Coppola, Simona and Amin, Ehsan and Pannone, Luca and Nouri, Kazem and Farina, Luciapia and Dvorsky, Radovan and Lepri, Francesca and Buchholzer, Marcel and Konopatzki, Raphael and Walsh, Laurence and Payne, Katelyn and Pierpont, Mary Ella and Vergano, Samantha Schrier and Langley, Katherine G and Larsen, Douglas and Farwell, Kelly D and Tang, Sha and Mroske, Cameron and Gallotta, Ivan and Di Schiavi, Elia and Della Monica, Matteo and Lugli, Licia and Rossi, Cesare and Seri, Marco and Cocchi, Guido and Henderson, Lindsay and Baskin, Berivan and Alders, Marielle and Mendoza-Londono, Roberto and Dupuis, Lucie and Nickerson, Deborah A and Chong, Jessica X and Meeks, Naomi and Brown, Kathleen and Causey, Tahnee and Cho, Megan T and Demuth, Stephanie and Digilio, Maria Cristina and Gelb, Bruce D and Bamshad, Michael J and Zenker, Martin and Ahmadian, Mohammad Reza and Hennekam, Raoul C and Tartaglia, Marco and Mirzaa, Ghayda M} } @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 {69, title = {De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects.}, journal = {PLoS Genet}, volume = {12}, year = {2016}, month = {2016 Apr}, pages = {e1005963}, abstract = {

Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32\% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk.

}, keywords = {Animals, Female, Heart Septal Defects, Heterozygote, Homozygote, Humans, Male, Mice, Mice, Knockout, Mutation, Pedigree}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1005963}, author = {Priest, James R and Osoegawa, Kazutoyo and Mohammed, Nebil and Nanda, Vivek and Kundu, Ramendra and Schultz, Kathleen and Lammer, Edward J and Girirajan, Santhosh and Scheetz, Todd and Waggott, Daryl and Haddad, Francois and Reddy, Sushma and Bernstein, Daniel and Burns, Trudy and Steimle, Jeffrey D and Yang, Xinan H and Moskowitz, Ivan P and Hurles, Matthew and Lifton, Richard P and Nickerson, Debbie and Bamshad, Michael and Eichler, Evan E and Mital, Seema and Sheffield, Val and Quertermous, Thomas and Gelb, Bruce D and Portman, Michael and Ashley, Euan A} } @article {147, title = {Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Nov}, pages = {1080-7}, abstract = {

The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80\% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.

}, keywords = {Adolescent, Adult, Alleles, Amino Acid Substitution, Child, DNA Mutational Analysis, Exome, Facies, Female, Genetic Association Studies, Genotype, Humans, Male, Models, Molecular, Mutation, Noonan Syndrome, Phenotype, Protein Conformation, Protein Interaction Domains and Motifs, Son of Sevenless Proteins, Young Adult}, issn = {1098-1004}, doi = {10.1002/humu.22834}, author = {Cordeddu, Viviana and Yin, Jiani C and Gunnarsson, Cecilia and Virtanen, Carl and Drunat, S{\'e}verine and Lepri, Francesca and De Luca, Alessandro and Rossi, Cesare and Ciolfi, Andrea and Pugh, Trevor J and Bruselles, Alessandro and Priest, James R and Pennacchio, Len A and Lu, Zhibin and Danesh, Arnavaz and Quevedo, Rene and Hamid, Alaa and Martinelli, Simone and Pantaleoni, Francesca and Gnazzo, Maria and Daniele, Paola and Lissewski, Christina and Bocchinfuso, Gianfranco and Stella, Lorenzo and Odent, Sylvie and Philip, Nicole and Faivre, Laurence and Vlckova, Marketa and Seemanova, Eva and Digilio, Cristina and Zenker, Martin and Zampino, Giuseppe and Verloes, Alain and Dallapiccola, Bruno and Roberts, Amy E and Cav{\'e}, H{\'e}l{\`e}ne and Gelb, Bruce D and Neel, Benjamin G and Tartaglia, Marco} } @article {225, title = {Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data.}, journal = {Circ Res}, volume = {115}, year = {2014}, month = {2014 Oct 24}, pages = {884-896}, abstract = {

RATIONALE: Congenital heart disease (CHD) is among the most common birth defects. Most cases are of unknown pathogenesis.

OBJECTIVE: To determine the contribution of de novo copy number variants (CNVs) in the pathogenesis of sporadic CHD.

METHODS AND RESULTS: We studied 538 CHD trios using genome-wide dense single nucleotide polymorphism arrays and whole exome sequencing. Results were experimentally validated using digital droplet polymerase chain reaction. We compared validated CNVs in CHD cases with CNVs in 1301 healthy control trios. The 2 complementary high-resolution technologies identified 63 validated de novo CNVs in 51 CHD cases. A significant increase in CNV burden was observed when comparing CHD trios with healthy trios, using either single nucleotide polymorphism array (P=7{\texttimes}10(-5); odds ratio, 4.6) or whole exome sequencing data (P=6{\texttimes}10(-4); odds ratio, 3.5) and remained after removing 16\% of de novo CNV loci previously reported as pathogenic (P=0.02; odds ratio, 2.7). We observed recurrent de novo CNVs on 15q11.2 encompassing CYFIP1, NIPA1, and NIPA2 and single de novo CNVs encompassing DUSP1, JUN, JUP, MED15, MED9, PTPRE SREBF1, TOP2A, and ZEB2, genes that interact with established CHD proteins NKX2-5 and GATA4. Integrating de novo variants in whole exome sequencing and CNV data suggests that ETS1 is the pathogenic gene altered by 11q24.2-q25 deletions in Jacobsen syndrome and that CTBP2 is the pathogenic gene in 10q subtelomeric deletions.

CONCLUSIONS: We demonstrate a significantly increased frequency of rare de novo CNVs in CHD patients compared with healthy controls and suggest several novel genetic loci for CHD.

}, keywords = {Case-Control Studies, Cohort Studies, DNA Copy Number Variations, Exome, Gene Frequency, Gene Regulatory Networks, Heart Defects, Congenital, Humans, Molecular Sequence Data, Polymorphism, Single Nucleotide}, issn = {1524-4571}, doi = {10.1161/CIRCRESAHA.115.304458}, author = {Glessner, Joseph T and Bick, Alexander G and Ito, Kaoru and Homsy, Jason and Rodriguez-Murillo, Laura and Fromer, Menachem and Mazaika, Erica and Vardarajan, Badri and Italia, Michael and Leipzig, Jeremy and DePalma, Steven R and Golhar, Ryan and Sanders, Stephan J and Yamrom, Boris and Ronemus, Michael and Iossifov, Ivan and Willsey, A Jeremy and State, Matthew W and Kaltman, Jonathan R and White, Peter S and Shen, Yufeng and Warburton, Dorothy and Brueckner, Martina and Seidman, Christine and Goldmuntz, Elizabeth and Gelb, Bruce D and Lifton, Richard and Seidman, Jonathan and Hakonarson, Hakon and Chung, Wendy K} } @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} }