Systematic Cardiac Phenotyping of Patients With Copy Number Variants in the 15q11.2 Breakpoint 1 to Breakpoint 2 Region: A Retrospective Cohort Study From Nine Pediatric Cardiac Centers.

Copy number variants, deletion or duplication, of the 15q11.2 BP1-BP2 region, which contains four highly conserved genes (NIPA1, NIPA2, CYFIP1 and TUBGCP5) proposed to be involved in cardiac development, are associated with congenital heart defects.

Microdeletions of the 15q11.2 BP1-BP2 region, adjacent to the Prader-Willi critical region, already have described neuropsychiatric associations and have been linked to potentially low-penetrance congenital heart disease. Four highly conserved genes in the region (NIPA1, NIPA2, CYFIP1 and TUBGCP5) have been proposed to be involved in cardiac development. This retrospective study examined cardiac defects in 50 patients carrying a 15q11.2 BP1-BP2 microdeletion (n = 37) or microduplication (n = 13), using the Cytogenomics of Cardiovascular Malformations (CCVM) Consortium registry, which includes patients with both an abnormal echocardiogram and abnormal chromosomal microarray findings. The microdeletion was enriched in the registry compared with its prevalence in a control population (OR = 3.9; p < 0.0001), with a significant increase in total anomalous pulmonary venous return among deletion carriers (OR = 13.0; p < 0.0001), while left ventricular outflow tract obstruction was increased in microduplication carriers (OR = 3.9; p = 0.02). The authors conclude that these results support an association between 15q11.2 BP1-BP2 copy number variants and congenital heart disease, including novel associations.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Recruiting from a registry that requires both an abnormal echocardiogram and an abnormal microarray introduces a major ascertainment bias: these odds ratios measure enrichment within an already cardiac population, not the absolute risk of congenital heart disease in a carrier. The numbers remain small, particularly the 13 duplications, and the left-sided obstruction association (p = 0.02) needs replication. In the clinic this does not yet justify systematic cardiac screening of every carrier, but it makes careful cardiac assessment reasonable when a 15q11.2 BP1-BP2 copy number variant is found, with particular attention to pulmonary venous return in deletion carriers.

Analysis by Dr Thibaut Benquey