Large-scale discovery of novel genetic causes of developmental disorders
Open accessAbstract
Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.
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This genotype-driven approach has revealed new disorders associated with more variable clinical presentation.
“This genotype-driven approach has revealed new disorders associated with more variable clinical presentation15,16.”
From A brief history of human disease genetics (2020) · cites this paper as [16]
In two previous studies using the same significance threshold, 26 novel developmental-disorder-associated genes were identified, and all are now regarded as diagnostic and have entered routine clinical practice.
“In two previous studies using the same significance threshold, we identified 26 novel DD-associated genes1,31. All 26 are now regarded as being diagnostic, and have entered routine clinical diagnostic practice.”
From Evidence for 28 genetic disorders discovered by combining healthcare and research data (2020) · cites this paper as [31]
Exome sequencing studies of ASD and severe neurodevelopmental disorders have identified risk genes, with genetic signals concentrated in constrained genes and shared between the two disorders.
“These studies have established that the genetic signals were concentrated in constrained genes and shared between the two disorders35,36.”
From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [35]
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- Authors
- Study, T. D. D. D.
- Corresponding author
- The Deciphering Developmental Disorders Study
- Venue
- Nature
- Published
- 2014-12-24
- Volume
- 519
- Issue
- 7542
- Pages
- 223-228
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5955210
- OpenAlex
- W2087216143
- Cited by
- 1,124
- References
- 26
- Citations by year
- 2026: 40 · 2025: 54 · 2024: 89 · 2023: 89 · 2022: 122 · 2021: 111 · 2020: 121 · 2019: 111 · 2018: 93 · 2017: 119 · 2016: 113 · 2015: 60 · 2014: 1
- FWCI
- 64.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust (091986, 098395, WT 098051, 100140, 100140/Z/12/Z)
- Scottish Government (CZD/16/6)
- Cancer Research UK (15934)
- National Institute for Health and Care Research (NF-SI-0510-10282, HICF-1009-003)
- Scottish Funding Council (HR03006)
- Chief Scientist Office, Scottish Government Health and Social Care Directorate (CZD/16/6)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- developmental disorders, undiagnosed genetic disorders, novel disease genes, chromosomal rearrangements, missense mutations, rare genetic disorders, genetic diagnosis, monogenic disorders, exome sequencing
- MeSH terms
- Adolescent, Animals, Carrier Proteins, Child, Developmental Disabilities, Child, Preschool, Chromosomal Proteins, Non-Histone, Chromosome Aberrations, DNA-Binding Proteins, Female, Genes, Dominant, United Kingdom, Humans, Infant, Infant, Newborn, Male, Nerve Tissue Proteins, Nuclear Proteins, Parents, Phosphoproteins, Repressor Proteins, Transcription Factors, Zebrafish, Genome, Human, Protein Serine-Threonine Kinases, Homeodomain Proteins, Gene Expression Regulation, Developmental, Cell Cycle Proteins, Transposases, Mutation, Missense, Guanine Nucleotide Exchange Factors, Dynamin I, Rare Diseases, DEAD-box RNA Helicases, Protein Phosphatase 2, Exome, Polycomb Repressive Complex 1
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