Increased Frequency of De Novo Copy Number Variants in Congenital Heart Disease by Integrative Analysis of Single Nucleotide Polymorphism Array and Exome Sequence Data

Glessner, Joseph T.; Bick, Alexander; Ito, Kei; Homsy, Jason; Rodríguez-Murillo, Laura; Fromer, Menachem; Mazaika, Erica; Vardarajan, Badri N.; Italia, Michael J.; Leipzig, Jeremy; DePalma, Steven R.; Golhar, Ryan; Sanders, Stephan; Yamrom, Boris; Ronemus, Michael; Iossifov, Ivan; Willsey, A. Jeremy; State, Matthew W.; Kaltman, Jonathan R.; White, Peter S.; Shen, Yufeng; Warburton, Dorothy; Brueckner, Martina; Seidman, Christine E.; Goldmuntz, Elizabeth; Gelb, Bruce D.; Lifton, Richard P.; Hákonarson, Hákon; Chung, Wendy K.

doi:10.1161/circresaha.115.304458

Cited by 230 publications

(224 citation statements)

References 69 publications

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“…It is known that many CNV disorders have pleiotropic effects on organ function, simultaneously predisposing to cardiac malformations, metabolic disorders, autism, schizophrenia, intellectual disability, and seizure disorders (9,10,(22)(23)(24). We previously detected an excess of CNV disorders in patients with congenital kidney malformations (15), but this study now implicates CNV disorders in the pathogenesis of clinically diverse forms of CKD.…”

Section: Discussionmentioning

confidence: 64%

Genomic imbalances in pediatric patients with chronic kidney disease

et al. 2015

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Section: Discussionmentioning

confidence: 64%

Genomic imbalances in pediatric patients with chronic kidney disease

et al. 2015

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“…However, CHD patient prognosis is variable, with long-term outcome shown to be dependent on patient intrinsic factors rather than surgical parameters (Newburger et al 2012;Marelli et al 2016). This is likely driven by genetic factors, given CHD is highly associated with chromosomal anomalies (Fahed et al 2013), and with copy number variants (Glessner et al 2014). In addition, CHD has been shown to have a high recurrence risk, with familial clustering indicating a genetic contribution (Gill et al 2003;Oyen et al 2009).…”

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confidence: 99%

Cilia and Ciliopathies in Congenital Heart Disease

Klena

Gibbs

2017

Cold Spring Harb Perspect Biol

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A central role for cilia in congenital heart disease (CHD) was recently identified in a largescale mouse mutagenesis screen. Although the screen was phenotype-driven, the majority of genes recovered were cilia-related, suggesting that cilia play a central role in CHD pathogenesis. This partly reflects the role of cilia as a hub for cell signaling pathways regulating cardiovascular development. Consistent with this, many cilia-transduced cell signaling genes were also recovered, and genes regulating vesicular trafficking, a pathway essential for ciliogenesis and cell signaling. Interestingly, among CHD-cilia genes recovered, some regulate left-right patterning, indicating cardiac left-right asymmetry disturbance may play significant roles in CHD pathogenesis. Clinically, CHD patients show a high prevalence of ciliary dysfunction and show enrichment for de novo mutations in cilia-related pathways. Combined with the mouse findings, this would suggest CHD may be a new class of ciliopathy.

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“…A few studies have evidenced rare CNVs in patients with nonsyndromic CHD using this method. [9][10][11][12][13][14][15][16] Here, we report a study performed in 316 children with nonsyndromic CHD and their normal parents. Our data show a high contribution of rare inherited but also de novo CNVs to human CHD and suggest a major role of Forkhead Box C1 (FOXC1) in the pathogenesis of CoA.…”

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confidence: 99%

Search for Rare Copy-Number Variants in Congenital Heart Defects Identifies Novel Candidate Genes and a Potential Role for FOXC1 in Patients With Coarctation of the Aorta

Sanchez-Castro¹,

Eldjouzi²,

Charpentier³

et al. 2016

Circ Cardiovasc Genet

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C ongenital heart defects (CHD) are the most common congenital malformations with an incidence of 0.5% to 1% of live births.1 They also are the first cause of mortality during the first year of life of newborns in developed countries.2 Despite therapeutic advances, CHD are associated with a high proportion of long term morbidity. Among CHD, a large subset involves the outflow tract (OFT). This heterogeneous group of malformations represents 20% to 30% of the CHD diagnosed in newborns.3 Transposition of the great arteries (TGA) accounts for 5% to 7% of all CHD 4 and is one of the most common cyanotic disorder diagnosed in the neonatal period with a prevalence of 0.2 per 1000 live births. The most common form of TGA is the dextro-looped type, which consists in a discordant ventriculoarterial connection implying that the aorta incorrectly arises from the right ventricle in an anterior and right-sided position, whereas the pulmonary artery incorrectly arises from the left ventricle in a posterior and left-sided position. By contrast to the normal heart in which both OFTs and great vessels show a dextral (right handed) spiralization, the great vessels in TGA present with a parallel course lacking normal spiralization. Coarctation Background-Congenital heart defects are the most frequent malformations among newborns and a frequent cause of morbidity and mortality. Although genetic variation contributes to congenital heart defects, their precise molecular bases remain unknown in the majority of patients. Methods and Results-We analyzed, by high-resolution array comparative genomic hybridization, 316 children with sporadic, nonsyndromic congenital heart defects, including 76 coarctation of the aorta, 159 transposition of the great arteries, and 81 tetralogy of Fallot, as well as their unaffected parents. We identified by array comparative genomic hybridization, and validated by quantitative real-time polymerase chain reaction, 71 rare de novo (n=8) or inherited (n=63) copy-number variants (CNVs; 50 duplications and 21 deletions) in patients. We identified 113 candidate genes for congenital heart defects within these CNVs, including BTRC, CHRNB3, CSRP2BP, ERBB2, ERMARD, GLIS3, PLN, PTPRJ, RLN3, and TCTE3. No de novo CNVs were identified in patients with transposition of the great arteries in contrast to coarctation of the aorta and tetralogy of Fallot (P=0.002; Fisher exact test). A search for transcription factor binding sites showed that 93% of the rare CNVs identified in patients with coarctation of the aorta contained at least 1 gene with FOXC1-binding sites. This significant enrichment (P<0.0001; permutation test) was not observed for the CNVs identified in patients with transposition of the great arteries and tetralogy of Fallot. We hypothesize that these CNVs may alter the expression of genes regulated by FOXC1. Foxc1 belongs to the forkhead transcription factors family, which plays a critical role in cardiovascular development in mice. Conclusions-These data suggest that deregulation of FOXC1 or its downstream ge...

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Increased Frequency of De Novo Copy Number Variants in Congenital Heart Disease by Integrative Analysis of Single Nucleotide Polymorphism Array and Exome Sequence Data

Cited by 230 publications

References 69 publications

Genomic imbalances in pediatric patients with chronic kidney disease

Genomic imbalances in pediatric patients with chronic kidney disease

Cilia and Ciliopathies in Congenital Heart Disease

Search for Rare Copy-Number Variants in Congenital Heart Defects Identifies Novel Candidate Genes and a Potential Role for FOXC1 in Patients With Coarctation of the Aorta

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