Genetic Evaluation and Use of Chromosome Microarray in Patients with Isolated Heart Defects: Benefits and Challenges of a New Model in Cardiovascular Care

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.

Fetal cardiac abnormalities: Genetic etiologies to be considered

“…Postnatal studies support a high yield of clinically relevant CNVs in both isolated and CHDs with associated anomalies, consistently higher in the latter group. 15 Studies find 3% to 14% of children with isolated CHDs have an underlying clinically significant CNV, 28 while such pathogenic CNVs occur in 15% to 20% of children with extracardiac features. 29,30 In the prenatal setting, the clinical yield of CMA in CHDs is growing.…”

“…In the prenatal setting, decisions about additional genetic testing after a negative CMA are not straightforward. Additional genetic testing, including sequencing of single genes associated with known conditions, NGS panels and/or WES can be presented provided pretest and posttest counseling appropriately cover the key concepts . When a specific syndrome is suspected, targeted testing can be undertaken.…”

“…10,13,14 In the remaining 75% to 80% isolated CHDs, there is mainly a multifactorial origin. 15 In a case series, a genetic etiology was found in around 10% of cases, of which two-third were a chromosomal anomaly and one-third were an identifiable nonchromosomal genetic syndrome. [10][11][12]14 The percentage of multifactorial etiology may continue to decrease as applications of genetic testing to the isolated cardiac anomaly group reveal underlying genetic causes and syndromes.…”

“…Additional genetic testing, including sequencing of single genes associated with known conditions, NGS panels and/or WES can be presented provided pretest and posttest counseling appropriately cover the key concepts. 15 When a specific syndrome is suspected, targeted testing can be undertaken. history of a prior undiagnosed fetus (or child) affected with a major single anomaly or multiple anomalies and a recurrence of similar anomalies in the current pregnancy without a genetic diagnosis after karyotype or CMA.…”

Congenital Heart Disease: Genetic Aspect and Prenatal and Postnatal Counseling

“…However, standard karyotype has an estimated 3% detection rate for pathogenic chromosome abnormalities. Conventional chromosome analysis detects wellknown chromosome aneuploidies in about 10% of cases of CHDs [126]. with the advent and feasibility of newer technology, karyotype maybe used less and become replaced.…”