Federated analysis of autosomal recessive coding variants in 29,745 developmental disorder patients from diverse populations
Autosomal recessive coding variants are well-known causes of rare disorders. We quantified the contribution of these variants to developmental disorders in a large, ancestrally diverse cohort comprising 29,745 trios, of whom 20.4% had genetically inferred non-European ancestries. The estimated fraction of patients attributable to exome-wide autosomal recessive coding variants ranged from ~2-19% across genetically inferred ancestry groups and was significantly correlated with average autozygosity. Established autosomal recessive developmental disorder-associated (ARDD) genes explained 84.0% of the total autosomal recessive coding burden, and 34.4% of the burden in these established genes was explained by variants not already reported as pathogenic in ClinVar. Statistical analyses identified two novel ARDD genes: KBTBD2 and ZDHHC16. This study expands our understanding of the genetic architecture of developmental disorders across diverse genetically inferred ancestry groups and suggests that improving strategies for interpreting missense variants in known ARDD genes may help diagnose more patients than discovering the remaining genes.
Authors
- Vincent D. Ustach (ORCID: https://orcid.org/0000-0001-8299-3998)
- V. Kartik Chundru (ORCID: https://orcid.org/0000-0002-6348-5565)
- Daniel Shiloh Malawsky (ORCID: https://orcid.org/0000-0003-4421-8688)
- Klaudia Walter (ORCID: https://orcid.org/0000-0003-4448-0301)
- Emilie M. Wigdor (ORCID: https://orcid.org/0000-0002-2370-0128)
- Bruno Reversade (ORCID: https://orcid.org/0000-0002-4070-7997)
- Kaitlin E. Samocha (ORCID: https://orcid.org/0000-0002-1704-3352)
- Petr Danecek (ORCID: https://orcid.org/0000-0002-4159-1666)
- Eugene J. Gardner (ORCID: https://orcid.org/0000-0001-9671-1533)
- Kyle Retterer (ORCID: https://orcid.org/0000-0001-5252-2001)
- Ruth Y. Eberhardt (ORCID: https://orcid.org/0000-0001-6152-1369)
- Eamonn Sheridan (ORCID: https://orcid.org/0000-0002-7237-6280)
- Helen V. Firth (ORCID: https://orcid.org/0000-0002-6410-0882)
- Caroline F. Wright (ORCID: https://orcid.org/0000-0003-2958-5076)
- Emmanuelle Szenker‐Ravi (ORCID: https://orcid.org/0000-0003-4839-737X)
- Sarah Lindsay (ORCID: https://orcid.org/0000-0002-0965-3070)
- Matthew E. Hurles (ORCID: https://orcid.org/0000-0002-2333-7015)
- Hilary C. Martin (ORCID: https://orcid.org/0000-0002-4454-9084)
- María J. Guillen Sacoto (ORCID: https://orcid.org/0000-0003-3772-8815)
- Akif Ayaz
- Peter Bauer (ORCID: https://orcid.org/0000-0003-2811-1354)
- Aida M. Bertoli‐Avella (ORCID: https://orcid.org/0000-0001-9544-1877)
- Rebecca I. Torene (ORCID: https://orcid.org/0000-0002-4370-3625)
- Kirsty McWalter (ORCID: https://orcid.org/0000-0002-1654-9036)
- Zhancheng Zhang
- Hildur Ólafsdóttir
- Ismail Hakki Akbeyaz
- Aaisha Ibrahim Al Balushi
- Dilşad Türkdoğan
Institutions
- Broad Institute (US)
- Geisinger Medical Center (US)
- University of Leeds (GB)
- deCODE Genetics (Iceland) (IS)
- University of Exeter (GB)
- Chapel Allerton Hospital (GB)
- Royal Devon and Exeter Hospital (GB)
- St James's University Hospital (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Wellcome Sanger Institute (GB)
- Istanbul Medipol University (TR)
- University of Oxford (GB)
- Massachusetts General Hospital (US)
- Royal Hospital (OM)
- Centogene (Germany) (DE)
- Addenbrooke's Hospital (GB)
- MRC Epidemiology Unit (GB)
- University of Rostock (DE)
- King Abdullah University of Science and Technology (SA)
- Marmara University (TR)
Publication Details
- Journal
- Nature Genetics
- Published
- 2024-09-23
- DOI
- https://doi.org/10.1038/s41588-024-01910-8
- Citations
- 9
- Primary Topic
- Genomics and Rare Diseases
- Type
- article
- Field-Weighted Citation Impact
- 4.95
Funders
- Wellcome Trust
- National Institute for Health and Care Research
- Department of Health and Social Care