Rare Copy Number Variants Contribute to Congenital Left-Sided Heart Disease

Hitz, Marc‐Phillip; Lemieux-Perreault, Louis-Philippe; Marshall, Christian R.; Feroz-Zada, Yassamin; Davies, Robbie; Yang, Shi Wei; Lionel, Anath C.; DʹAmours, Guylaine; Lemyre, Emmanuelle; Cullum, Rebecca; Bigras, Jean‐Luc; Thibeault, Maryse; Chétaille, Philippe; Montpetit, Alexandre; Khairy, Paul; Overduin, Bert; Klaassen, Sabine; Hoodless, Pamela A.; Awadalla, Philip; Hussin, Julie; Idaghdour, Youssef; Nemer, Mona; Stewart, Alexandre F.R.; Boerkoel, Cornelius F.; Scherer, Stephen W.; Richter, Andréa; Dubé, Marie‐Pierre; Andelfinger, Grégor

doi:10.1371/journal.pgen.1002903

Cited by 116 publications

(117 citation statements)

References 47 publications

(60 reference statements)

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“…This supports the hypothesis that converging and accumulating rare genomic and epigenetic variants may disrupt regulatory networks during heart development, ultimately leading to CHD. 12,13,50 Because we excluded the noncoding regions of our custom array, we were not able to detect chromosomal imbalances involving regulatory elements, which is a limitation of our study. According to the multifactorial origin of CHD, environmental factors during embryo development may also be considered as contributing factors to CHD in addition to genetic variations.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

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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“…Genome-wide [20][21][22] and gene-centric 23 copy number variants (CNV) were tested on a series of CHD with criteria to infer causality based either on de novo deletion/duplication in sporadic cases or familial segregation in multiplex cases. These studies could confirm the involvement of known CHD genes and discover new genes and genomic regions.…”

Section: Discussionmentioning

confidence: 99%

A systematic variant screening in familial cases of congenital heart defects demonstrates the usefulness of molecular genetics in this field

Malti¹,

Liu²,

Doray³

et al. 2015

Eur J Hum Genet

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The etiology of congenital heart defect (CHD) combines environmental and genetic factors. So far, there were studies reporting on the screening of a single gene on unselected CHD or on familial cases selected for specific CHD types. Our goal was to systematically screen a proband of familial cases of CHD on a set of genetic tests to evaluate the prevalence of disease-causing variant identification. A systematic screening of GATA4, NKX2-5, ZIC3 and Multiplex ligation-dependent probe amplification (MLPA) P311 Kit was setup on the proband of 154 families with at least two cases of non-syndromic CHD. Additionally, ELN screening was performed on families with supravalvular arterial stenosis. Twenty-two variants were found, but segregation analysis confirmed unambiguously the causality of 16 variants: GATA4 (1 × ), NKX2-5 (6 × ), ZIC3 (3 × ), MLPA (2 × ) and ELN (4 × ). Therefore, this approach was able to identify the causal variant in 10.4% of familial CHD cases. This study demonstrated the existence of a de novo variant even in familial CHD cases and the impact of CHD variants on adult cardiac condition even in the absence of CHD. This study showed that the systematic screening of genetic factors is useful in familial CHD cases with up to 10.4% elucidated cases. When successful, it drastically improved genetic counseling by discovering unaffected variant carriers who are at risk of transmitting their variant and are also exposed to develop cardiac complications during adulthood thus prompting long-term cardiac follow-up. This study provides an important baseline at dawning of the next-generation sequencing era.

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“…Auch die Anzahl krankheitsverursachender CNV ist überschaubar. Zwar konnten vereinzelt große De-novo-Ereignisse bei isoliert auftretenden Fällen mit Fallot-Tetralogie [17], Linksherzfehlbildungen, wie dem hypoplastischen Linksherzsyndrom (HLHS) [18], oder anderen sporadisch auftretenden AHFFällen gefunden werden [19], doch insgesamt bleibt die Ätiologie unklar.…”

Section: Nicht-syndromale Strukturelle Herzfehlerunclassified