Repurposing Normal Chromosomal Microarray Data to Harbor Genetic Insights into Congenital Heart Disease

SIMPLE SUMMARY: About 15% of people born with congenital heart disease (CHD) have a specific genetic abnormality called a copy number variant. Most of their genetic tests, called chromosomal microarrays (CMAs), are considered normal. However, we suspected that some very small genetic deletions might be linked to CHD even though they were not reported in the test results. To investigate this, we investigated genetic test data from 319 patients with CHD. Then, we focused on genes in these small deletions that were somehow related to CHD, based on certain criteria like their association with CHD, their expression level in fetal hearts, and the potential impact of losing these genes. After analyzing the data, we found that these unreported small genetic deletions were slightly more likely to involve genes known to be related to CHD and also genes that might be important but were not recognized before. Our study suggests that “normal” genetic test data, which is readily available, can be valuable for discovering new genetic links to CHD. Also, smaller genetic deletions should be given more clinical attention for potential implications in CHD. ABSTRACT: About 15% of congenital heart disease (CHD) patients have a known pathogenic copy number variant. The majority of their chromosomal microarray (CMA) tests are deemed normal. Diagnostic interpretation typically ignores microdeletions smaller than 100 kb. We hypothesized that unreported microdeletions are enriched for CHD genes. We analyzed “normal” CMAs of 1762 patients who were evaluated at a pediatric referral center, of which 319 (18%) had CHD. Using CMAs from monozygotic twins or replicates from the same individual, we established a size threshold based on probe count for the reproducible detection of small microdeletions. Genes in the microdeletions were sequentially filtered by their nominal association with a CHD diagnosis, the expression level in the fetal heart, and the deleteriousness of a loss-of-function mutation. The subsequent enrichment for CHD genes was assessed using the presence of known or potentially novel genes implicated by a large whole-exome sequencing study of CHD. The unreported microdeletions were modestly enriched for both known CHD genes and those of unknown significance identified using their de novo mutation in CHD patients. Our results show that readily available “normal” CMA data can be a fruitful resource for genetic discovery and that smaller deletions should receive more attention in clinical evaluation.