Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA

Abstract

Congenital heart defects (CHD) are the most common congenital anomalies in liveborn children. In contrast to syndromic CHD (SCHD), the genetic basis of isolated CHD (ICHD) is complex, and the underlying pathogenic mechanisms appear intricate and are incompletely understood. Next to rare Mendelian conditions, somatic mosaicism or a complex multifactorial genetic architecture are assumed for most ICHD. We performed exome sequencing (ES) in 73 parent–offspring ICHD trios using proband DNA extracted from cardiac tissue. We identified six germline de novo variants and 625 germline rare inherited variants with ‘damaging’ in silico predictions in cardiac-relevant genes expressed in the developing human heart. There were no CHD-relevant somatic variants. Transmission disequilibrium testing (TDT) and association testing (AT) yielded no statistically significant results, except for the AT of missense variants in cilia genes. Somatic mutations are not a common cause of ICHD. Rare de novo and inherited protein-damaging variants may contribute to ICHD, possibly as part of an oligogenic or polygenic disease model. TDT and AT failed to provide informative results, likely due to the lack of power, but provided a framework for future studies in larger cohorts. Overall, the diagnostic value of ES on cardiac tissue is limited in individual ICHD cases.

Uncovering the Genetic Basis of Congenital Heart Disease: Recent Advancements and Implications for Clinical Management

“… 99 , 100 , 101 , 102 , 103 , 104 WES can identify gene variants inherited oligogenically. 105 Gifford et al., 100 for example, identified NKX2.5 as a modifier in the oligogenic inheritance of left ventricular noncompaction cardiomyopathy using WES. The extent of differentiation of hiPSC-CM is limited, and its maturity level is equal to cardiomyocytes found in the fetal heart; therefore, disease phenotypes, particularly those acquired later in life, may not fully manifest.…”

Discovery of GJC1 (Cx45) as a New Gene Underlying Congenital Heart Disease and Arrhythmias

“…Genetic defects responsible for CHD include aneuploidy (presence of an additional chromosome, absence of a chromosome, or deletion/duplication of one arm of a chromosome), copy number variation (deletion or duplication of a segment of a chromosome), and genetic mutations [ 44 , 45 , 46 ]. To date, pathogenic mutations in over 100 genes have been involved in the occurrence of CHD, of which most encode cardiac transcription factors, cell adhesion molecules, signaling pathway proteins, and cardiac structural proteins essential for cardiovascular morphogenesis [ 44 , 45 , 46 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ]. However, CHD is of pronounced genetic heterogeneity, and the genetic determinants causative for CHD in a significant proportion of cases remain to be identified.…”