Systematic Cardiac Phenotyping of Patients With Copy Number Variants in the 15q11.2 Breakpoint 1 to Breakpoint 2...

Microdeletions impacting 15q11.2 breakpoint (BP) 1 to BP2, adjacent to the Prader-Willi critical region, have previously described neuropsychiatric associations, with potential low penetrance presentations of congenital heart disease (CHD) also identified. Four highly conserved genes in the region (NIPA1, NIPA2, CYFIP1, and TUBGCP5) have been proposed to be involved in cardiac development, yet further exploration is needed to better define cardiac phenotypes of patients with copy number variants (CNVs) in the 15q11.2 BP1-BP2 region. This study examines cardiac defects in 50 patients with microdeletion (n = 37) or microduplication (n = 13) in 15q11.2 BP1-BP2, utilizing data from the Cytogenomics of Cardiovascular Malformations (CCVM) Consortium registry, composed of patients with both abnormal echocardiogram and chromosomal microarray findings. The microdeletion was found to be enriched in the registry compared to prevalence in a control population (OR = 3.9; p < 0.0001), with a significant increase of total anomalous pulmonary venous return (TAPVR) in patients who were carriers of the microdeletion (OR = 13.0; p < 0.0001). Left ventricular outflow tract obstruction (LVOTO) was increased in individuals with the microduplication (OR = 3.9; p = 0.02). Our results provide evidence for association of CHD with 15q11.2 BP1-BP2 CNVs, with novel associations reported.