Impact of Genetic Diagnosis on Clinical Management of Patients With Congenital Heart Disease

Congenital heart disease is a group of pathologies characterized by structural malformations of the heart or great vessels. These alterations occur during the embryonic period and are the most frequently observed severe congenital malformations, the main cause of neonatal mortality due to malformation, and the second most frequent congenital malformations overall after malformations of the central nervous system. The severity of different types of congenital heart disease varies depending on the combination of associated anatomical defects. The causes of these malformations are usually considered multifactorial, but genetic variants play a key role. Currently, use of high-throughput genetic technologies allows identification of pathogenic aneuploidies, deletions/duplications of large segments, as well as rare single nucleotide variants. The high incidence of congenital heart disease as well as the associated complications makes it necessary to establish a diagnosis as early as possible to adopt the most appropriate measures in a personalized approach. In this review, we provide an exhaustive update of the genetic bases of the most frequent congenital heart diseases as well as other syndromes associated with congenital heart defects, and how genetic data can be translated to clinical practice in a personalized approach.

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The Diagnostic Yield of Prenatal Genetic Technologies in Congenital Heart Disease: A Prospective Cohort Study

Fetal Diagnosis and Therapy ◽

10.1159/000512488 ◽

2021 ◽

pp. 1-8

Author(s):

Fionnuala Mone ◽

Bethany K. Stott ◽

Susan Hamilton ◽

Anna N. Seale ◽

Elizabeth Quinlan-Jones ◽

...

Keyword(s):

Congenital Heart Disease ◽

Cohort Study ◽

Heart Disease ◽

Prospective Cohort Study ◽

Prospective Cohort ◽

Congenital Heart ◽

Diagnostic Yield ◽

Genetic Diagnosis ◽

Uncertain Significance ◽

Conotruncal Anomalies

Introduction: The objective was to evaluate: (i) the proportion of prenatally diagnosed congenital heart disease (CHD) associated with an abnormal quantitative fluorescence-PCR (QF-PCR), chromosome microarray (CMA), and exome sequencing (ES) result; and (ii) the diagnostic yield of these technologies based on CHD category and presence of extra-cardiac anomalies (ECAs). Methods: This prospective cohort study was set across 12 UK foetal medicine centres. All cases underwent QF-PCR, CMA, and ES, and the diagnostic yield in n = 147 cases of prenatally diagnosed CHD was assessed. Results: In 34.7% (n = 51/147), a genetic diagnosis was obtained. Using a stepwise testing strategy, the diagnostic yield for QF-PCR, CMA, and ES was 15.6% (n = 23/147), 13.7% (n = 17/124), and 10.2% (n = 11/107), respectively. Abnormal QF-PCR/shunt (septal) defects 31.4% (n = 11/35), p = 0.046, and abnormal CMA/conotruncal anomalies 22.7% (n = 10/44), p = 0.04, had significant associations. Monogenic variants were commonest in complex CHD 36.4% (n = 4/11). Multisystem CHD had a greater diagnostic yield overall compared to isolated OR 2.41 (95% CI, 1.1–5.1), particularly in association with brain and gastrointestinal tract anomalies. The proportion of variants of uncertain significance was 4.7% (n = 5/107) with ES, with none in the CMA group. Conclusion: In the era of prenatal ES, there remains an important role for QF-PCR and CMA. Identification of monogenic pathologic variants further allows delineation of prognosis in CHD.

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An Atlas of Congenital Heart Disease

PEDIATRICS ◽

10.1542/peds.32.6.1077 ◽

1963 ◽

Vol 32 (6) ◽

pp. 1077-1077

Author(s):

NORMAN J. SISSMAN

Keyword(s):

Congenital Heart Disease ◽

Heart Disease ◽

Clinical Management ◽

Congenital Heart ◽

Pathological Examination ◽

Children's Hospital ◽

The Past ◽

Present Volume ◽

Children’S Hospital

Despite the vast experience accumulated during the past decade with all aspects of the lives and deaths of patients with congenital heart disease, there is still room for the clarification and direction that careful, informed, imaginative analysis of the results of pathological examination of postmortem material can give to the clinical management of these patients. Dr. Sherman has made a notable contribution in this area with the present volume. The atlas was compiled from 503 specimens collected in the Museum of Congenital Heart Disease at the Children's Hospital in Pittsburgh since 1954.

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Functional genomics and gene-environment interaction highlight the complexity of congenital heart disease caused by Notch pathway variants

Human Molecular Genetics ◽

10.1093/hmg/ddz270 ◽

2019 ◽

Vol 29 (4) ◽

pp. 566-579 ◽

Cited By ~ 8

Author(s):

Gavin Chapman ◽

Julie L M Moreau ◽

Eddie I P ◽

Justin O Szot ◽

Kavitha R Iyer ◽

...

Keyword(s):

Congenital Heart Disease ◽

Heart Disease ◽

Congenital Heart ◽

Cultured Cells ◽

Heart Defects ◽

Genetic Diagnosis ◽

Notch Pathway ◽

Environment Interaction ◽

Gene Environment Interaction ◽

Gene Environment

Abstract Congenital heart disease (CHD) is the most common birth defect and brings with it significant mortality and morbidity. The application of exome and genome sequencing has greatly improved the rate of genetic diagnosis for CHD but the cause in the majority of cases remains uncertain. It is clear that genetics, as well as environmental influences, play roles in the aetiology of CHD. Here we address both these aspects of causation with respect to the Notch signalling pathway. In our CHD cohort, variants in core Notch pathway genes account for 20% of those that cause disease, a rate that did not increase with the inclusion of genes of the broader Notch pathway and its regulators. This is reinforced by case-control burden analysis where variants in Notch pathway genes are enriched in CHD patients. This enrichment is due to variation in NOTCH1. Functional analysis of some novel missense NOTCH1 and DLL4 variants in cultured cells demonstrate reduced signalling activity, allowing variant reclassification. Although loss-of-function variants in DLL4 are known to cause Adams-Oliver syndrome, this is the first report of a hypomorphic DLL4 allele as a cause of isolated CHD. Finally, we demonstrate a gene-environment interaction in mouse embryos between Notch1 heterozygosity and low oxygen- or anti-arrhythmic drug-induced gestational hypoxia, resulting in an increased incidence of heart defects. This implies that exposure to environmental insults such as hypoxia could explain variable expressivity and penetrance of observed CHD in families carrying Notch pathway variants.

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Use of an Administrative Database to Determine Clinical Management and Outcomes in Congenital Heart Disease

World Journal for Pediatric and Congenital Heart Surgery ◽

10.1177/2150135111414065 ◽

2011 ◽

Vol 2 (4) ◽

pp. 593-596 ◽

Cited By ~ 7

Author(s):

Howard P. Gutgesell ◽

Diane G. Hillman ◽

Kimberly E. McHugh ◽

Peter Dean ◽

G. Paul Matherne

Keyword(s):

Congenital Heart Disease ◽

Heart Disease ◽

Clinical Management ◽

Congenital Heart ◽

Administrative Database

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Genetic Testing Protocol Reduces Costs and Increases Rate of Genetic Diagnosis in Infants with Congenital Heart Disease

Pediatric Cardiology ◽

10.1007/s00246-017-1685-7 ◽

2017 ◽

Vol 38 (7) ◽

pp. 1465-1470 ◽

Cited By ~ 12

Author(s):

Gabrielle C. Geddes ◽

Donald Basel ◽

Peter Frommelt ◽

Aaron Kinney ◽

Michael Earing

Keyword(s):

Congenital Heart Disease ◽

Heart Disease ◽

Genetic Testing ◽

Congenital Heart ◽

Genetic Diagnosis ◽

Testing Protocol

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Partial Trisomy 11q in a Female Infant with Robin Sequence and Congenital Heart Disease

The Cleft Palate-Craniofacial Journal ◽

10.1597/1545-1569_1992_029_0077_ptiafi_2.3.co_2 ◽

1992 ◽

Vol 29 (1) ◽

pp. 77-79 ◽

Cited By ~ 1

Author(s):

Robert Wallerstein ◽

Franklin Desposito ◽

Hana Aviv ◽

Maryann Schenk ◽

Donna F. Wallerstein

Keyword(s):

Congenital Heart Disease ◽

Heart Disease ◽

Clinical Management ◽

Congenital Heart ◽

Partial Trisomy ◽

Female Infant ◽

Cardiac Defects ◽

Cardiac Anomalies ◽

Robin Sequence

We describe the clinical and cytogenetic findings in a female infant with partial trisomy 11q, Robin sequence, cardiac anomalies, and other minor malformations. We compare the phenotypic similarities of our case to a series by Pihko et al. (1981), who reported on 20 cases with partial trisomy 11q with similar associated craniofacial and cardiac defects. We conclude that genetic etiologies for patients diagnosed with the Robin sequence may be more common than previously believed and that initial karyotyping should be performed to aid both diagnosis and clinical management. In addition, the pattern of Robin sequence and cardiac defects may be specifically suggestive of partial trisomy 11q.

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Risk Factors for Candidemia in Pediatric Patients With Congenital Heart Disease

Infection Control and Hospital Epidemiology ◽

10.1086/505094 ◽

2006 ◽

Vol 27 (6) ◽

pp. 576-580 ◽

Cited By ~ 14

Author(s):

Lucía García-San Miguel ◽

Javier Cobo ◽

Isabel Martos ◽

Enrique Otheo ◽

Alfonso Muriel ◽

...

Keyword(s):

Risk Factors ◽

Congenital Heart Disease ◽

Heart Disease ◽

Confidence Interval ◽

Antibiotic Therapy ◽

Clinical Management ◽

Odds Ratio ◽

Congenital Heart ◽

Tertiary Care ◽

Surveillance Culture

Objective.To identify the main risk factors for the acquisition of candidemia in children with congenital heart disease (CHD) in order to improve the clinical management of these patients.Design.A case-control study.Setting.A large tertiary-care referral center in Spain with a pediatric intensive care unit (PICU) to which more than 500 children with CHD are admitted annually.Patients.All patients had CHD and were admitted to the PICU during 1995-2000. Case patients were defined as patients with candidemia, and control patients were defined as patients without candidemia.Results.Twenty-eight case patients and 47 control subjects were included in the study. Case patients were younger (mean age [ ± SD], 12.5 ± 32.0 vs 38.0 ± 48.0 months;P< .01) and had a longer median PICU stay (19 vs 4 days;P< .01), and a greater percentage of case patients previously hadCandidaspecies isolated from specimens other than blood (eg, bronchial aspirates, urine, or skin specimens) (39% vs 4%;P<.01). Severity of clinical condition, as measured by the Therapeutic Intervention Scoring System (TISS) 1 week after PICU admission (odds ratio, 1.15; 95% confidence interval, 1.05-1.26;P<.01), and receipt of antibiotic treatment for more than 5 days (odds ratio, 13.42; 95% confidence interval, 1.31-137.13;P= .03) were independently associated with the development of candidemia.Conclusions.Patients with CHD who have a high TISS score 1 week after PICU admission and patients who have received prolonged antibiotic therapy should be considered at high risk for candidemia. Our results suggest that shorter courses of antibiotic therapy, routine surveillance culture forCandidaspecies, and initiation of preemptive or empirical antifungal treatment could help in the clinical management of these patients.

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