Proteome-wide assessment of differential missense variant clustering in neurodevelopmental disorders and cancer
Prior studies examining genomic variants suggest that some proteins contribute to both neurodevelopmental disorders (NDDs) and cancer. While there are several potential etiologies, here, we hypothesize that missense variation in proteins occurs in different clustering patterns, resulting in distinct phenotypic outcomes. This concept was first explored in 1D protein space and expanded using 3D protein structure models. Missense de novo variants were examined from 39,883 families with NDDs and missense somatic variants from 10,543 sequenced tumors covering five The Cancer Genome Atlas (TCGA) cancer types and two Catalog of Somatic Mutations in Cancer (COSMIC) pan-cancer aggregates of tissue types. We find 18 proteins with differential missense variation clustering in NDDs compared to cancers and 19 in cancers relative to NDDs. These proteins may be important for detailed assessments in thinking of future prognostic and therapeutic applications. We establish a framework for interpreting missense patterns in NDDs and cancer, using advances in 3D protein structure prediction.
Authors
- Zachary L. Payne (ORCID: https://orcid.org/0000-0001-6328-2533)
- Jeffrey K. Ng
- Rachel Karchin (ORCID: https://orcid.org/0000-0002-5069-1239)
- Yoonhoo Chang (ORCID: https://orcid.org/0000-0002-6215-8466)
- Titilope M. Akinwe (ORCID: https://orcid.org/0000-0002-9406-7497)
- David H. Gutmann (ORCID: https://orcid.org/0000-0002-3127-5045)
- Tychele N. Turner
- Elvisa Mehinovic (ORCID: https://orcid.org/0000-0001-5083-4888)
- Hillary B. Heins (ORCID: https://orcid.org/0009-0009-5648-4239)
- Christina A. Gurnett (ORCID: https://orcid.org/0000-0001-9129-315X)
- Yilin Chen (ORCID: https://orcid.org/0000-0001-8154-4402)
- Juana Manuel (ORCID: https://orcid.org/0009-0000-0023-1245)
Institutions
- Johns Hopkins University (US)
- Washington University in St. Louis (US)
- Johns Hopkins Medicine (US)
- Sidney Kimmel Comprehensive Cancer Center (US)
Publication Details
- Journal
- Cell Genomics
- Published
- 2025-03-11
- DOI
- https://doi.org/10.1016/j.xgen.2025.100807
- Citations
- 3
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 5.45
Funders
- Simons Foundation
- Simons Foundation Autism Research Initiative
- Instituto Tecnológico de Costa Rica
- National Institutes of Health
- Intellectual and Developmental Disabilities Research Center
- McDonnell Center for Cellular and Molecular Neurobiology, Washington University in St. Louis
- National Institute of Mental Health
- National Cancer Institute
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine in St. Louis