Repurposing Normal Chromosomal Microarray Data to Harbor Genetic Insights into Congenital Heart Disease
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...
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MDPI AG
2023-09-01
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| Series: | Biology |
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| Online Access: | https://www.mdpi.com/2079-7737/12/10/1290 |
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| author | Nephi A. Walton Hoang H. Nguyen Sara S. Procknow Darren Johnson Alexander Anzelmi Patrick Y. Jay |
| author_facet | Nephi A. Walton Hoang H. Nguyen Sara S. Procknow Darren Johnson Alexander Anzelmi Patrick Y. Jay |
| author_sort | Nephi A. Walton |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T21:25:54Z |
| format | Article |
| id | doaj.art-d551611b75e04d4a96ee22f50fb8b688 |
| institution | Directory Open Access Journal |
| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-10T21:25:54Z |
| publishDate | 2023-09-01 |
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| spelling | doaj.art-d551611b75e04d4a96ee22f50fb8b6882023-11-19T15:43:11ZengMDPI AGBiology2079-77372023-09-011210129010.3390/biology12101290Repurposing Normal Chromosomal Microarray Data to Harbor Genetic Insights into Congenital Heart DiseaseNephi A. Walton0Hoang H. Nguyen1Sara S. Procknow2Darren Johnson3Alexander Anzelmi4Patrick Y. Jay5Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USADepartment of Pediatrics, UT Southwestern Medical Center, Dallas, TX 75390, USADepartment of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USAGenomic Medicine Institute, Geisinger, Danville, PA 17822, USADepartment of Medicine, Thomas Jefferson University Hospitals, Philadelphia, PA 19107, USADepartment of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USAAbout 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.https://www.mdpi.com/2079-7737/12/10/1290chromosome microarraycongenital heart diseasedata mininggenetic diagnosisprecision medicinegenetic testing |
| spellingShingle | Nephi A. Walton Hoang H. Nguyen Sara S. Procknow Darren Johnson Alexander Anzelmi Patrick Y. Jay Repurposing Normal Chromosomal Microarray Data to Harbor Genetic Insights into Congenital Heart Disease Biology chromosome microarray congenital heart disease data mining genetic diagnosis precision medicine genetic testing |
| title | Repurposing Normal Chromosomal Microarray Data to Harbor Genetic Insights into Congenital Heart Disease |
| title_full | Repurposing Normal Chromosomal Microarray Data to Harbor Genetic Insights into Congenital Heart Disease |
| title_fullStr | Repurposing Normal Chromosomal Microarray Data to Harbor Genetic Insights into Congenital Heart Disease |
| title_full_unstemmed | Repurposing Normal Chromosomal Microarray Data to Harbor Genetic Insights into Congenital Heart Disease |
| title_short | Repurposing Normal Chromosomal Microarray Data to Harbor Genetic Insights into Congenital Heart Disease |
| title_sort | repurposing normal chromosomal microarray data to harbor genetic insights into congenital heart disease |
| topic | chromosome microarray congenital heart disease data mining genetic diagnosis precision medicine genetic testing |
| url | https://www.mdpi.com/2079-7737/12/10/1290 |
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