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 Article see p 301 These single-gene syndromes are good examples of how human genetic studies have been very successful at identifying genes causing typical, highly penetrant Mendelian diseases. A few individuals with isolated, nonsyndromic CVMs possess this mode of inheritance, and such families have proven useful at identifying CVM causing genes such as NOTCH1 and ZIC3. 5,6 However, these types of families are few and far between. The vast majority of families have a strong genetic component for their CVM, measured by high recurrence rates and high heritability,7 but a complex pattern of inheritance that may include reduced penetrance, polygenic inheritance (genetic burden with susceptibility thresholds), and combinations of gene and environment interactions and modifiers. Even aneuploidies known to cause CVMs, such as trisomy 21 (T21), have far from universal occurrence of CVMs. For example, although CVMs in general, and atrioventricular septal defects in particular, are known to be associated with T21, …