Abstract
Congenital heart defects (CHDs) are common birth defects and result in significant morbidity and global economic impact. Genetic factors play a role in most CHDs; however, identification of these factors has been historically slow due to technological limitations and incomplete understanding of the impact of human genomic variation on normal and abnormal cardiovascular development. The advent of chromosome microarray (CMA) brought tremendous gains in identifying chromosome abnormalities in a variety of human disorders and is now considered part of a standard evaluation for individuals with multiple congenital anomalies and/or neurodevelopmental disorders. Several studies investigating use of CMA found that this technology can identify pathogenic copy-number variations (CNVs) in up to 15–20% of patients with CHDs with other congenital anomalies. However, there have been fewer studies exploring the use of CMA for patients with isolated CHDs. Recent studies have shown that the diagnostic yield of CMA in individuals with seemingly isolated CHD is lower than in individuals with CHDs and additional anomalies. Nevertheless, positive CMA testing in this group supports chromosome variation as one mechanism underlying the development of isolated, non-syndromic CHD – either as a causative or risk-influencing genetic factor. CMA has also identified novel genomic variation in CHDs, shedding light on candidate genes and pathways involved in cardiac development and malformations. Additional studies are needed to further address this issue. Early genetic diagnosis can enhance the medical management of patients and potentially provide crucial information about recurrence. This information is critical for genetic counseling of patients and family members. In this review, we review CMA for the non-genetics cardiology provider, offer a summary of CNV in isolated CHDs, and advocate for the use of CMA as part of the cardiovascular genetics evaluation of patients with isolated CHDs. We also provide perspective regarding the benefits and challenges that lie ahead for this model in the clinical setting.
Highlights
Congenital heart defects (CHDs) are a common group of human malformations with significant morbidity and economic impact [1,2,3]
AS, aortic stenosis; ASD, atrial septal defect; AVSD, atrioventricular septal defect; CHD, congenital heart defect; CoA, coarctation of the aorta; D-TGA, dextro-transposition of the great arteries; HLHS, hypoplastic left heart syndrome; PAPVR, partial anomalous pulmonary venous return; PDA, patent ductus arteriosus; PS, pulmonary stenosis; TAPVR, total anomalous pulmonary venous return; TOF, tetralogy of Fallot; VSD, ventricular septal defect. aIt was unclear if these reports included patients with clinical diagnoses of syndromic disorders (i.e., DiGeorge syndrome for 22q11/2 deletion or Alagille syndrome for the 20p12.2 deletion)
Another challenge when using chromosome microarray (CMA) in the CHD population is the “one-hit fallacy” or the notion that any specific CHD is caused by one particular genetic variation alone
Summary
Congenital heart defects (CHDs) are a common group of human malformations with significant morbidity and economic impact [1,2,3]. There are examples of apparently isolated CHDs that were found to have CNVs overlapping known syndromic regions [e.g., 22q11.2 deletion and duplication, 16p11.2 duplication; see Silversides et al [40]] It is unclear if those patients had been evaluated for and/or diagnosed clinically with a genetic syndrome, or they had been unrecognized or only presented with mild features. Further studies with meticulous phenotyping and goals to assess broad classes of CHDs lesions should be undertaken to further refine this estimate This highlights the critical importance of involvement of clinical geneticists in the evaluation of seemingly isolated CHDs. Chromosome microarray is recommended as a first-tier clinical genetic test in cases of isolated CHDs due to the relatively high rate of detection of pathogenic CNVs. Positive results in the patient with isolated CHDs can provide important information for practitioners and family members when making decisions regarding ongoing care and family planning. Confirmed or putative candidate CHD types in study genes for CHDs noted by authors (limited list)
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