Integrating healthcare and research genetic data empowers the discovery of 28 novel developmental disorders
Open accessAbstract
Summary: De novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated genes only account for a minority of the observed excess of such DNMs. To identify novel DD-associated genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, and developed a simulation-based statistical test to identify gene-specific enrichments of DNMs. We identified 285 significantly DD-associated genes, including 28 not previously robustly associated with DDs. Despite detecting more DD-associated genes than in any previous study, much of the excess of DNMs of protein-coding genes remains unaccounted for. Modelling suggests that over 1,000 novel DD-associated genes await discovery, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of dominant DDs.
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De novo missense mutations in TRIO significantly disrupted the exons preceding or containing the RhoGEF domain.
“De novo missense mutations in TRIO significantly disrupted the exons preceding or containing the RhoGEF domain (Figure 5C) 36,37 , and de novo missense mutations in GRIN2A cluster at the base of the ion channel with the most mutations in the exon encoding for the pore of the complex (Figure 5D).”
From Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia (2020) · cites this paper as [36]
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- Authors
- Kaplanis, J., Samocha, K. E., Wiel, L., Zhang, Z., Arvai, K. J., Eberhardt, R. Y., Gallone, G., Lelieveld, S. H., Martin, H. C., McRae, J. F., Short, P. J., Torene, R. I., de Boer, E., Danecek, P., Gardner, E. J., Huang, N., Lord, J., Martincorena, I., Pfundt, R., Reijnders, M. R. F., Yeung, A., Yntema, H. G., Study, D., Vissers, L. E. L. M., Juusola, J., Wright, C. F., Brunner, H. G., Firth, H. V., FitzPatrick, D. R., Barrett, J. C., Hurles, M. E., Gilissen, C., & Retterer, K.
- Affiliations
- Wellcome Sanger Institute (GB)
- Radboud University Nijmegen (NL)
- Victorian Clinical Genetics Services (AU)
- Radboud University Medical Center (NL)
- University of Exeter (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Western General Hospital (GB)
- Corresponding author
- Hurles, Matthew E.
- ORCID
- Kaplanis, Joanna
- Samocha, Kaitlin E.
- Wiel, Laurens
- Zhang, Zhancheng
- Arvai, Kevin J.
- Eberhardt, Ruth Y.
- Lelieveld, Stefan H.
- Martin, Hilary C.
- McRae, Jeremy F.
- Short, Patrick J.
- Torene, Rebecca I.
- Danecek, Petr
- Gardner, Eugene J.
- Huang, Ni
- Lord, Jenny
- Martincorena, Iñigo
- Pfundt, Rolph
- Reijnders, Margot R. F.
- Yeung, Alison
- Yntema, Helger G.
- Vissers, Lisenka E. L. M.
- Juusola, Jane
- Wright, Caroline F.
- Brunner, Han G.
- Firth, Helen V.
- FitzPatrick, David R.
- Barrett, Jeffrey C.
- Hurles, Matthew E.
- Gilissen, Christian
- Retterer, Kyle
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2019-10-16
- OpenAlex
- W3014392250
- Cited by
- 36
- References
- 44
- Citations by year
- 2026: 1 · 2024: 1 · 2022: 5 · 2021: 18 · 2020: 10 · 2019: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Funders
- European Commission (HICF-1009-003, HORIZON2020, 779257)
- Radboud Universitair Medisch Centrum
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- developmental disorders, de novo mutations, parent-offspring trios, exome sequencing, penetrance
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