Prevalence and architecture of de novo mutations in developmental disorders
Open accessAbstract
The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year.
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Exome studies identify a higher frequency of disruptive de novo variants in severe NDD than in ASD.
“exome studies identify a higher frequency of disruptive de novo variants in severe NDD than in ASD (Deciphering Developmental Disorders Study, 2017)”
From Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2020) · cites this paper as Deciphering Developmental Disorders Study, 2017
The paper’s Abstract reports exome sequencing in severe developmental disorders and enrichment for damaging de novo mutations, with approximately half of estimated pathogenic coding mutations disrupting gene function. It does not report a frequency comparison with ASD; ASD studies appear in the References, but those entries do not establish the claimed higher frequency. (LLM, conf=0.85)
Experimental — accuracy not yet measuredA similar sex effect in severe developmental disorders is entirely explained by a relatively small number of DD genes.
“However, a similar effect is observed in severe developmental disorders more generally and is entirely explained by a relatively small number of genes significantly associated with severe developmental disorders (that is, DD genes)48.”
From Genetic correlates of phenotypic heterogeneity in autism (2022) · cites this paper as [48]
93 developmental disorder risk genes with genome-wide significance were obtained from the Deciphering Developmental Disorders Study.
“Genes that harbor de novo protein disrupting variation in developmental disorders (DD) were obtained from the Deciphering Developmental Disorders Study (93 DD risk genes with genome-wide significance)64.”
From A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles (2020) · cites this paper as [64]
The ID/DD cohorts evaluated in the Satterstrom and Coe studies overlapped almost completely; each study used samples from five previously published studies, and four of the five were the same studies, accounting for 99% of the samples.
“In fact, the ID/DD cohorts evaluated in these two studies overlapped almost completely; each study used samples from five previously published studies, and four of the five were the same studies, accounting for 99% of the samples.11, 12, 13, 14, 15, 16”
From Insufficient Evidence for “Autism-Specific” Genes (2020) · cites this paper as [16]
Reduced reliance on multiplex pedigrees in favour of collections of affected cases, often with parents, has been decisive in identifying new dominant disorders, many previously considered recessive.
“Reduced reliance on multiplex pedigrees in favour of collections of affected cases, often with parents13, has proven decisive in identifying new dominant disorders, many of which were previously considered recessive14.”
From A brief history of human disease genetics (2020) · cites this paper as [14]
De novo mutations in protein-coding genes are an established cause of developmental disorders.
“De novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD)1.”
From Evidence for 28 genetic disorders discovered by combining healthcare and research data (2020) · cites this paper as [1]
About 42-48% of patients with severe developmental disorder have a pathogenic de novo mutation in a protein-coding gene.
“It has previously been estimated that ~42-48% of patients with a severe developmental disorder (DD) have a pathogenic de novo mutation (DNM) in a protein coding gene1,2.”
From Evidence for 28 genetic disorders discovered by combining healthcare and research data (2020) · cites this paper as [1]
Known developmental-disorder-associated genes explain only a minority of the observed excess of de novo mutations.
“However, known DD-associated genes only account for a minority of the observed excess of such DNMs1,2.”
From Evidence for 28 genetic disorders discovered by combining healthcare and research data (2020) · cites this paper as [1]
DeNovoWEST identified 281 significantly enriched genes in the full cohort, 18 more than the previous method.
“We first applied DeNovoWEST to all individuals in our cohort and identified 281 significantly enriched genes, 18 more than when using our previous method1 (Supplementary Fig. 5; Fig. 1a).”
From Evidence for 28 genetic disorders discovered by combining healthcare and research data (2020) · cites this paper as [1]
The rate of nonsynonymous de novo mutations in consensus autosomal genes was higher in females than males (OR = 1.16, p = 4.4 × 10-7).
“The rate of nonsynonymous DNMs in consensus autosomal genes was significantly higher in females than males (OR = 1.16, p = 4.4 × 10-7, Fisher’s exact test; Fig. 1e), as noted previously1.”
From Evidence for 28 genetic disorders discovered by combining healthcare and research data (2020) · cites this paper as [1]
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 [1]
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“Consistent with these observations, exome studies identify a higher frequency of disruptive de novo variants in severe NDD than in ASD (Deciphering Developmental Disorders Study, 2017).”
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- Authors
- Study, D. D. D.
- Corresponding author
- Deciphering Developmental Disorders Study
- Venue
- Nature
- Published
- 2017-01-25
- Volume
- 542
- Issue
- 7642
- Pages
- 433-438
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6016744
- OpenAlex
- W2581649032
- Cited by
- 1,480
- References
- 51
- Citations by year
- 2026: 71 · 2025: 111 · 2024: 166 · 2023: 144 · 2022: 152 · 2021: 187 · 2020: 200 · 2019: 178 · 2018: 181 · 2017: 86
- FWCI
- 22.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- Open Research Exeter (University of Exeter) (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Apollo
- Funders
- Wellcome Trust (WT 098051)
- National Institute for Health and Care Research (NF-SI-0515-10035)
- Medical Research Council (MR/M014568/1)
- Engineering and Physical Sciences Research Council (1380788)
- 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
- de novo mutations, developmental disorders, prevalence, diagnostic yield, parental age, sex differences, pathogenic variants, phenotypic diversity
- MeSH terms
- Protein Phosphatase 2C, Adolescent, Adult, Autoantigens, Child, Developmental Disabilities, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins, Female, Humans, Male, Middle Aged, Mutation, Nerve Tissue Proteins, Parents, Phenotype, Histone-Lysine N-Methyltransferase, Repressor Proteins, Sex Characteristics, Transcription Factors, Cohort Studies, Prevalence, CDC2 Protein Kinase, Sequence Analysis, DNA, Homeodomain Proteins, ras GTPase-Activating Proteins, Heredity, Casein Kinase II, Myeloid-Lymphoid Leukemia Protein, DEAD-box RNA Helicases, Young Adult, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Exome
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