Noncoding variants and sulcal patterns in congenital heart disease: Machine learning to predict functional impact
Neurodevelopmental impairments associated with congenital heart disease (CHD) may arise from perturbations in brain developmental pathways, including the formation of sulcal patterns. While genetic factors contribute to sulcal features, the association of noncoding <i>de novo</i> variants (ncDNVs) with sulcal patterns in people with CHD remains poorly understood. Leveraging deep learning models, we examined the predicted impact of ncDNVs on gene regulatory signals. Predicted impact was compared between participants with CHD and a jointly called cohort without CHD. We then assessed the relationship of the predicted impact of ncDNVs with their sulcal folding patterns. ncDNVs predicted to increase H3K9me2 modification were associated with larger disruptions in right parietal sulcal patterns in the CHD cohort. Genes predicted to be regulated by these ncDNVs were enriched for functions related to neuronal development. This highlights the potential of deep learning models to generate hypotheses about the role of noncoding variants in brain development.
Authors
- Martina K. Brueckner (ORCID: https://orcid.org/0000-0003-0347-5389)
- Hao Huang (ORCID: https://orcid.org/0000-0002-9103-4382)
- Caitlin K. Rollins (ORCID: https://orcid.org/0000-0002-0500-0056)
- Kiho Im (ORCID: https://orcid.org/0000-0002-9239-8970)
- Sarah U. Morton (ORCID: https://orcid.org/0000-0002-7816-2646)
- Elizabeth Goldmuntz (ORCID: https://orcid.org/0000-0003-2936-4396)
- P. Ellen Grant (ORCID: https://orcid.org/0009-0005-7577-1226)
- Jane W. Newburger (ORCID: https://orcid.org/0000-0002-7794-9017)
- Amy E. Roberts (ORCID: https://orcid.org/0000-0001-5827-8521)
- Martin Tristani‐Firouzi (ORCID: https://orcid.org/0000-0001-5916-442X)
- George Arthur Porter Jr. (ORCID: https://orcid.org/0000-0003-0726-9988)
- Steven R. DePalma (ORCID: https://orcid.org/0000-0002-0381-5016)
- Ashok Panigrahy (ORCID: https://orcid.org/0000-0003-1966-6681)
- Donald J. Hagler (ORCID: https://orcid.org/0000-0002-0331-3294)
- Enrique Mondragon‐Estrada (ORCID: https://orcid.org/0009-0004-5592-1728)
- Patrick S. McQuillen (ORCID: https://orcid.org/0000-0002-8837-364X)
- Bruce D. Gelb (ORCID: https://orcid.org/0000-0001-8527-5027)
- Mark W. W. Russell (ORCID: https://orcid.org/0000-0003-4855-9260)
- Thomas A. Miller (ORCID: https://orcid.org/0000-0001-5498-7021)
- Wendy K. Chung
- John D. Cleveland
Institutions
- University of Southern California (US)
- Boston Children's Hospital (US)
- Primary Children's Hospital (US)
- Maine Medical Center (US)
- Children's Hospital of Philadelphia (US)
- Harvard University (US)
- University of California, San Francisco (US)
- University of Utah (US)
- University of Michigan (US)
- University of Rochester Medical Center (US)
- Yale University (US)
- University of California San Diego (US)
- Child Health and Development Institute (US)
- Children's Hospital of Pittsburgh (US)
- University of Pittsburgh Medical Center (US)
- C. S. Mott Children's Hospital (US)
- University of Pennsylvania (US)
- Philadelphia University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- iScience
- Published
- 2024-12-28
- DOI
- https://doi.org/10.1016/j.isci.2024.111707
- Citations
- 2
- Primary Topic
- Congenital heart defects research
- Type
- article
- Field-Weighted Citation Impact
- 0.47
Funders
- American Heart Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Center for Research Resources
- National Center for Advancing Translational Sciences