Chromosomal Imbalances in Patients with Congenital Cardiac Defects: A Meta-analysis Reveals Novel Potential Critical Regions Involved in Heart Development

Thorsson, Thor; Russell, William; El-Kashlan, Nour; Soemedi, Rachel; Levine, Jonathan; Geisler, Stefanie; Ackley, Todd; Tomita‐Mitchell, Aoy; Rosenfeld, Jill A.; Töpf, Ana; Tayeh, Marwan K.; Goodship, Judith A.; Innis, Jeffrey W.; Keavney, Bernard; Russell, Mark W.

doi:10.1111/chd.12179

Cited by 25 publications

(28 citation statements)

References 48 publications

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“…Heart disease patients with distal deletion 22q11.2 have a broad spectrum of cardiac defects such as septal defects, tetralogy of Fallot, and conotruncal defects [Breckpot et al, 2012]. The deletion involving only the TOP3B gene was reported in 2 patients in the study by Thorsson et al [2015], and both presented CHD. However, the role of TOP3B in cardiac development still needs to be further studied because, even though TOP3B is also expressed in the heart, deletions or mutations of this gene are more frequently described in patients with neurological developmental delay [O'Roak et al, 2012;Stoll et al, 2013].…”

Section: Discussionmentioning

confidence: 96%

Major Contribution of Genomic Copy Number Variation in Syndromic Congenital Heart Disease: The Use of MLPA as the First Genetic Test

et al. 2017

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Congenital heart disease (CHD) is the most common congenital disorder among live births. When associated with extracardiac abnormalities, it is characterized as a syndromic heart disease (syndromic CHD) and corresponds to 25% of all liveborn infants with a heart defect. The etiology in about 65% of the cases still remains unknown, and in about 35% of the patients, it is associated with genetic factors. In the present study, MLPA and SNP-array techniques were used to investigate a group of 47 patients with syndromic CHD. In total, 16 defects (34%) were identified, of which 12 (25.5%) were classified as pathogenic or probably pathogenic. The most frequent abnormalities were 22q11.2 deletion (22q11.2 deletion syndrome) and 7q11.23 deletion (Williams-Beuren syndrome). We also show that rarer malformations may be associated with syndromic CHD, such as 14q32.33 deletion as well as 17q25.3, 15q11.2 (BP1-BP2), 22q13.31, and 12p13.31 (SLC2A3) duplications. The present study demonstrates that CNVs are important causal factors and should be studied in patients with syndromic CHD. Furthermore, the use of MLPA as a first screening test was appropriate, as this less expensive technology detected 11 of the 12 pathogenic abnormalities (91.6%).

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Section: Discussionmentioning

confidence: 96%

Major Contribution of Genomic Copy Number Variation in Syndromic Congenital Heart Disease: The Use of MLPA as the First Genetic Test

et al. 2017

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“…One attempt at a meta-analysis identified dozens of putatively associated loci. 52 Other CNVs appear so rarely that recurrence has not yet been observed. Most studies have reported only CNVs involving autosomes; sex chromosome copy number findings may also be relevant to CHD.…”

Section: Genome-wide Cnv In Chdmentioning

confidence: 99%

“…38,39,45,47,50,55,57,67,68 As for all CNVs associated with CHD, the expression is variable, even within families, for both cardiac anomalies and other phenotypes, and is not necessarily correlated with the length of the CNV. 38,40,47,52,67,69 1q21.1 duplications are rare in control populations, e.g., in five out of 18,828 controls (0.027%) from three studies, where some controls were not screened for disease (reviewed in ref 67). Although it is uncertain if any single gene at this locus can be designated as truly causal, the most evidence points to the GJA5 gene that encodes connexin 40, 38,68 a cardiac gap junction protein expressed in the right ventricular outflow tract.…”

Section: Genome-wide Cnv In Chdmentioning

confidence: 99%

The importance of copy number variation in congenital heart disease

Costain

Silversides

2016

npj Genomic Med

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Congenital heart disease (CHD) is the most common class of major malformations in humans. The historical association with large chromosomal abnormalities foreshadowed the role of submicroscopic rare copy number variations (CNVs) as important genetic causes of CHD. Recent studies have provided robust evidence for these structural variants as genome-wide contributors to all forms of CHD, including CHD that appears isolated without extra-cardiac features. Overall, a CNV-related molecular diagnosis can be made in up to one in eight patients with CHD. These include de novo and inherited variants at established (chromosome 22q11.2), emerging (chromosome 1q21.1), and novel loci across the genome. Variable expression of rare CNVs provides support for the notion of a genetic spectrum of CHD that crosses traditional anatomic classification boundaries. Clinical genetic testing using genome-wide technologies (e.g., chromosomal microarray analysis) is increasingly employed in prenatal, paediatric and adult settings. CNV discoveries in CHD have translated to changes to clinical management, prognostication and genetic counselling. The convergence of findings at individual gene and at pathway levels is shedding light on the mechanisms that govern human cardiac morphogenesis. These clinical and research advances are helping to inform whole-genome sequencing, the next logical step in delineating the genetic architecture of CHD.

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“…Only two other cases of HEY2 duplications with molecular cytogenetic descriptions have been previously reported in the literature [Thorsson et al, 2014]. Although these cases may provide some additional evidence that HEY2 duplications may contribute to the development of clinical phenotypes, their usefulness is limited by the large sizes of the chromosome 6q duplications involved, the presence of large or clinically relevant deletions on other chromosomes in the same individual and a paucity of clinical information.…”

Section: Discussionmentioning

confidence: 99%

Duplication of HEY2 in cardiac and neurologic development

Jordan

Rosenfeld

Lalani

et al. 2015

American J of Med Genetics Pt A

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HEY2 is a basic helix-loop-helix (bHLH) transcription factor that plays an important role in the developing mammalian heart and brain. In humans, nonsynonymous mutations in HEY2 have been described in patients with atrial ventricular septal defects, and a subset of individuals with chromosomal deletions involving HEY2 have cardiac defects and cognitive impairment. Less is known about the potential effects of HEY2 overexpression. Here, we describe a female child with tetralogy of Fallot who developed severe right ventricular outflow tract obstruction due to a combination of infundibular and valvular pulmonary stenosis. She was also noted to have hypotonia, lower extremity weakness, fine motor delay and speech delay. A copy number variation (CNV) detection analysis followed by real-time quantitative PCR analysis revealed a single gene duplication of HEY2. This is the only duplication involving HEY2 identified in our database of over 70,000 individuals referred for CNV analysis. In the developing heart, overexpression of HEY2 is predicted to cause decreased expression of the cardiac transcription factor GATA4 which, in turn, has been shown to cause tetralogy of Fallot. In mice, misexpression of Hey2 in the developing brain leads to inhibition of neurogenesis and promotion of gliogenesis. Hence, duplication of HEY2 may be a contributing factor to both the congenital heart defects and the neurodevelopmental problems evident in our patient. These results suggest that individuals with HEY2 duplications should be screened for congenital heart defects and monitored closely for evidence of developmental delay and/or cognitive impairment.

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Chromosomal Imbalances in Patients with Congenital Cardiac Defects: A Meta-analysis Reveals Novel Potential Critical Regions Involved in Heart Development

Cited by 25 publications

References 48 publications

Major Contribution of Genomic Copy Number Variation in Syndromic Congenital Heart Disease: The Use of MLPA as the First Genetic Test

Major Contribution of Genomic Copy Number Variation in Syndromic Congenital Heart Disease: The Use of MLPA as the First Genetic Test

The importance of copy number variation in congenital heart disease

Duplication of HEY2 in cardiac and neurologic development

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