Cardiac Defects and Genetic Syndromes: Old Uncertainties and New Insights

Abstract

Recent advances in understanding the genetic causes and anatomic subtypes of cardiac defects have revealed new links between genetic etiology, pathogenetic mechanisms and cardiac phenotypes. Although the same genetic background can result in different cardiac phenotypes, and similar phenotypes can be caused by different genetic causes, researchers’ effort to identify specific genotype–phenotype correlations remains crucial. In this review, we report on recent advances in the cardiac pathogenesis of three genetic diseases: Down syndrome, del22q11.2 deletion syndrome and Ellis–Van Creveld syndrome. In these conditions, the frequent and specific association with congenital heart defects and the recent characterization of the underlying molecular events contributing to pathogenesis provide significant examples of genotype–phenotype correlations. Defining these correlations is expected to improve diagnosis and patient stratification, and it has relevant implications for patient management and potential therapeutic options.

New Molecular and Organelle Alterations Linked to Down Syndrome Heart Disease

“…On the other hand, ZBTB21 has been shown to interact with PPP2R2B, which, in Drosophila , regulates the WNT/β-catenin signaling pathway. This pathway has been described as necessary for cardiac differentiation of human embryonic stem cells (ESCs) ( Calcagni et al, 2021 ). Additional analysis of copy number variants (CNV) has also shown that neither an individual chromosome 21 CNV nor any individual gene intersected by a CNV was associated with AVSD in DS ( Rambo-Martin et al, 2018 ).…”

“…Additional analysis of copy number variants (CNV) has also shown that neither an individual chromosome 21 CNV nor any individual gene intersected by a CNV was associated with AVSD in DS ( Rambo-Martin et al, 2018 ). In general, it has been suggested that CHD development is the result of a multifactorial model, with a cumulative effect in multiple risk alleles that exert minor or major contributions ( Rambo-Martin et al, 2018 ; Calcagni et al, 2021 ). Altogether, these findings suggest that cardiac defects in DS are not the result of the overexpression of just one gene, but of a set of them.…”

“…differentiation of human embryonic stem cells (ESCs) (Calcagni et al, 2021). Additional analysis of copy number variants (CNV) has also shown that neither an individual chromosome 21 CNV nor any individual gene intersected by a CNV was associated with AVSD in DS (Rambo-Martin et al, 2018).…”

Syndromic and Non-Syndromic Patients with Repaired Tetralogy of Fallot: Does It Affect the Long-Term Outcome?

“…Tetralogy of Fallot (ToF), the most common cyanotic congenital heart disease (CHD), can be associated with various genetic syndromes [1,2]. The most frequent ones are del22q11 deletion (Di George) syndrome and Down syndrome (DS) in 15% and 7% of cases, respectively, followed by Noonan, Holt-Oram, and VACTERL syndromes [1][2][3][4][5][6][7].…”

“…Tetralogy of Fallot (ToF), the most common cyanotic congenital heart disease (CHD), can be associated with various genetic syndromes [1,2]. The most frequent ones are del22q11 deletion (Di George) syndrome and Down syndrome (DS) in 15% and 7% of cases, respectively, followed by Noonan, Holt-Oram, and VACTERL syndromes [1][2][3][4][5][6][7]. Previously, an association has been reported between the presence of a genetic syndrome in patients with ToF and additional risks to the primary repair [8][9][10][11][12] due to the presence of associated anatomical abnormalities, immunodeficiency, or anomalies of pulmonary vascular resistance [10][11][12].…”