Modifying Mendel: approaches for identification of susceptibility alleles for human cardiovascular malformations.

Congenital cardiovascular malformations (CVMs) are the most common birth defect, affecting approximately 8 per 1000 live births. Roughly 25% of CVMs occur in the context of multiple congenital anomalies or as part of a genetic syndrome, while the other 75% of individuals present as an isolated, nonsyndromic CVM.1 Genomic disorders comprise the majority of syndomic CVMs, exemplified by aneuploidies such as trisomy 21 (Down syndrome) or monosomy X (Turner syndrome) and copy number variations (CNVs) such as deletion 22q11.2 (Velocardiofacial syndrome) and deletion 7q11.23 (Williams syndrome). There are also a few phenotypically well-characterized syndromes with CVMs that occur due to pathogenic variants in a single gene. These include the group of Noonan, Costello, and Cardiofaciocutaneous syndromes resulting from mutations in genes coding for proteins of the Ras pathway, and Holt-Oram syndrome which is caused by mutations in the gene TBX5.2–4