scholarly journals Burden of potentially pathologic copy number variants is higher in children with isolated congenital heart disease and significantly impairs covariate-adjusted transplant-free survival

2016 ◽  
Vol 151 (4) ◽  
pp. 1147-1151.e4 ◽  
Author(s):  
Daniel Seung Kim ◽  
Jerry H. Kim ◽  
Amber A. Burt ◽  
David R. Crosslin ◽  
Nancy Burnham ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Copy Number ◽  
Congenital Heart ◽  
Copy Number Variants ◽  
Free Survival

scholarly journals Contribution of Global Rare Copy-Number Variants to the Risk of Sporadic Congenital Heart Disease

2012 ◽  
Vol 91 (3) ◽  
pp. 489-501 ◽  
Author(s):  
Rachel Soemedi ◽  
Ian J. Wilson ◽  
Jamie Bentham ◽  
Rebecca Darlay ◽  
Ana Töpf ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Copy Number ◽  
Congenital Heart ◽  
Copy Number Variants

scholarly journals Copy Number Variants and Exome Sequencing Analysis in Six Pairs of Chinese Monozygotic Twins Discordant for Congenital Heart Disease

2017 ◽  
Vol 20 (6) ◽  
pp. 521-532 ◽  
Author(s):  
Yuejuan Xu ◽  
Tingting Li ◽  
Tian Pu ◽  
Ruixue Cao ◽  
Fei Long ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Exome Sequencing ◽  
Copy Number ◽  
Congenital Heart ◽  
Copy Number Variants ◽  
Genetic Mutation ◽  
Sequencing Analysis ◽  
Susceptibility Loci ◽  
Mz Twins

Congenital heart disease (CHD) is one of the most common birth defects. More than 200 susceptibility loci have been identified for CHDs, yet a large part of the genetic risk factors remain unexplained. Monozygotic (MZ) twins are thought to be completely genetically identical; however, discordant phenotypes have been found in MZ twins. Recent studies have demonstrated genetic differences between MZ twins. We aimed to test whether copy number variants (CNVs) and/or genetic mutation differences play a role in the etiology of CHDs by using single nucleotide polymorphism (SNP) genotyping arrays and whole exome sequencing of twin pairs discordant for CHDs. Our goal was to identify mutations present only in the affected twins, which could identify novel candidates for CHD susceptibility loci. We present a comprehensive analysis for the CNVs and genetic mutation results of the selected individuals but detected no consistent differences within the twin pairs. Our study confirms that chromosomal structure or genetic mutation differences do not seem to play a role in the MZ twins discordant for CHD.

scholarly journals De Novo Damaging Variants, Clinical Phenotypes, and Post-Operative Outcomes in Congenital Heart Disease

2020 ◽  
Vol 13 (4) ◽  
Author(s):  
Marko T. Boskovski ◽  
Jason Homsy ◽  
Meena Nathan ◽  
Lynn A. Sleeper ◽  
Sarah Morton ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Heart Surgery ◽  
De Novo ◽  
Open Heart Surgery ◽  
Copy Number Variants ◽  
Hazard Ratio ◽  
Free Survival ◽  
Cardiac Anomalies

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 ( P =5.63×10 −12 ). 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; P =5.33×10 −04 ) and longer times to final extubation (hazard ratio, 0.74; P =0.005). As de novo variants had a significant interaction with extra-cardiac anomalies for transplant-free survival ( P =0.003), de novo variants conveyed no additional risk for transplant-free survival for patients with these anomalies (adjusted hazard ratio, 1.96; P =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; P =1.61×10 −05 ) 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.

Array CGH as a first-tier test for neonates with congenital heart disease

2013 ◽  
Vol 25 (1) ◽  
pp. 115-122 ◽  
Author(s):  
Kristine K. Bachman ◽  
Stephanie J. DeWard ◽  
Constantinos Chrysostomou ◽  
Ricardo Munoz ◽  
Suneeta Madan-Khetarpal
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Cytogenetic Analysis ◽  
Copy Number ◽  
Congenital Heart ◽  
Clinical Care ◽  
Copy Number Variants ◽  
Comparative Genomic Hybridisation ◽  
Comparative Genomic ◽  
Array Comparative Genomic Hybridisation

AbstractObjectiveEfficient diagnosis of an underlying genetic aetiology in a patient with congenital heart disease is essential to optimising clinical care. Copy number variants are one aetiology of congenital heart disease; the majority are identifiable by targeted fluorescence in situ hybridisation or array comparative genomic hybridisation, not by classical cytogenetic analysis. This study assessed the utility of array comparative genomic hybridisation as a first-tier diagnostic test for neonates with congenital heart disease.Study designA prospective chart review of neonates with congenital heart disease in the Cardiac Intensive Care Unit at Children’s Hospital of Pittsburgh of UPMC was performed. Patients were tested by array comparative genomic hybridisation and classical cytogenetic analysis simultaneously. Data collected included all chromosome abnormalities detected, physical examination findings, and imaging results. McNemar’s test was used to compare detection of array comparative genomic hybridisation and classical cytogenetic analysis.ResultsOf 45 patients, three (6.7%) had an abnormality detected by classical cytogenetic analysis and an additional 10 (22.2%) had a copy number variant detected by array comparative genomic hybridisation, highlighting an increased detection rate (p=0.008). Several of these copy number variants had unclear clinical significance, requiring additional investigation. The prevalence of dysmorphology and/or comorbidity in this population was 72%. Identification of dysmorphic features was greater when assessed by a geneticist than by providers of different subspecialties.ConclusionsArray comparative genomic hybridisation has significant clinical utility as a first-tier test in this population, but it carries the potential for incidental findings and results of uncertain clinical significance. Collaboration between cardiologists and medical geneticists is essential to providing optimal clinical care.

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