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Prevalence and architecture of de novo mutations in developmental disorders


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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Figure 1: Association of phenotypes with the presence of DNMs that are probably pathogenic.
Figure 2: Genes exceeding genome-wide significance.
Figure 3: Excess of DNMs.
Figure 4: Prevalence of live births with DDs caused by dominant DNMs.

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We thank the families for their participation and patience. We are grateful to the Exome Aggregation Consortium for making their data available. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the UK Department of Health, and the Wellcome Trust Sanger Institute (grant WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the UK Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee and GEN/284/12, granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institutes for Health Research, through the Comprehensive Clinical Research Network. We thank the Sanger Human Genome Informatics team, the Sample Management team, the Illumina High-Throughput team, the New Pipeline Group team, the DNA pipelines team and the Core Sequencing team for their support in generating and processing the data. D.R.F. is funded through an MRC Human Genetics Unit program grant to the University of Edinburgh. Finally we acknowledge the contribution of two esteemed DDD clinical collaborators, J. Tolmie and L. Brueton, who died during the course of the study.

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Authors and Affiliations



Patient recruitment and phenotyping: M.Ah., U.A., H.A., R.A., M.Ba., S.Ba., D.Bar., A.Ba., P.B., D.Bat., C.Be., J.Be., B.B., M.B.-G., E.B., M.Bl., D.Boh., L.Bo., D.Bou., L.Br., A.Br., C.Br., K.B., D.J.B., J.Bu., N.Ca., B.C., K.C., D.C., A.Cl., S.Clas., J.C.-S., V.C., A.Coa., T.C., A.Col., M.N.C., F.C., N.Co., H.C., L.C., G.C., Y.C., M.D., T.D., R.D., S.Da., J.D., C.De., G.D., A.Di., A.Dob., A.Don., D.Donna., D.Donne., C.Do., A.Dou., S.Do., A.Du., J.E., S.El., I.E., F.E., K.E., S.Ev., T.F., R.F., F.F., N.F., A.Fry, A.Frye., C.G., L.Ga., N.G., R.G., H.G., J.G., D.G., A.G., P.G., L.Gr., R.Har., L.Ha., V.H., R.Haw., S.Hel., A.H., S.Hew., E.H., S.Holden, M.Ho., S.Holder, G.H., T.H., M.Hu., J.H., S.I., M.I., L.I., A.J., J.J., L.J., D.Joh., E.J., D.Jos., S.J., B.Ka., S.K., B.Ke., H.K., U.K., E.Kin., G.K., C.K., E.Kiv., A.K., D.Ku., V.K.A.K., K.L., W.L., A.L., C.La., M.L., D.L., C.Lo., G.L., S.A.L., A.Mag., E.Ma., A.Mal., S.Ma., K.Mark., K.Mart., U.M., E.Mc., V.Mc., M.M., R.M., K.Mc., S.McK., D.J.M., S.McN., C.M., S.Me., K.Me., Z.M., A.Mi., E.Mi., S.Moh., T.M., D.M., S.Mor., J.M., H.Mug., V.Mu., H.Mur., S.N., A.Ne., L.N., R.N.-E., A.No., R.O., C.O., K.-R.O., S.-M.P., M. J.P., C.Pa., J.Pa., S.Pa., J.Ph., D.T.P., C.Po., J.Po., N.P., K.P., S.Pr., A.Pri., A.Pro., H.P., O.Q., N.R., J.Rank., L.Ra., D.Ri., L.Ro., E.Rob., J.Ro., P.R., G.R., A.R., E.Ros., A.Sag., S.Sa., J.S., R.Sa., A.Sar., S.Sc., R.Sc., I.Sc., A.Selb., A.Sell., C.S., N.S., S.Sh., C.S.-S., E.Shea., D.S., E.Sher., I.Si., R.Si., Z.S., A.Sm., K.S., S.Sm., L.S., M.Sp., M.Sq., F.S., H.S., V.St., M.Su., V.Su., E.Sw., K.T.-B., C.Ta., R.T., M.Tein, I.K.T., J.T., M.Ti., S.T., A.T., B.T., C.Tu., P.T., C.Ty., A.V., V.V., P.Va., J.V., E.Wa., S.Wa., J.W., A.W., D.We., M.Wh., S.Wil., D.Wi., N.W., L.W., G.W., C.W., M.Wr., L.Y., M.Y., H.V.F. and D.R.F. Sample and data processing: S.Clay., T.W.F., E.P., D.Ra., K.A., D.M.B., T.B., P.J., N.K., L.E.M., A.R.T., A.P.B., S.Br., E.C., I.C., E.G., S.G., L.Hi., B.H., R.K., D.P., M.Po., J.Rand., G.J.S., S.Wid. and E.Wi. Validation experiments: J.F.M., E.P., D.Ra., A.Si., N.K. and C.F.W. Study design: M.Pa., H.V.F., C.F.W., D.R.F., J.C.B. and M.E.H. Method development and data analysis: J.F.M., S.Clay., T.W.F., J.K., E.P., D.Ra., A.Si., S.A., N.A., M.Al., P.J., W.D.J., D.Ki., T.S., J.A., D.d.V., L.He, R.R., G.J.S., P.Vi., C.N., H.V.F., C.F.W., D.R.F., J.C.B. and M.E.H. Data interpretation: J.F.M., H.V.F., C.F.W., D.R.F., J.C.B. and M.E.H. Writing: J.F.M., C.F.W., D.R.F. and M.E.H. Experimental and analytical supervision: M.Pa., H.V.F., C.F.W., D.R.F., J.C.B. and M.E.H. Project Supervision: M.E.H.

Corresponding author

Correspondence to Matthew E. Hurles.

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Competing interests

M.E.H. is a co-founder of, consultant to, and holds shares in, Congenica Ltd, a genetics diagnostic company.

Additional information

Reviewer Information Nature thanks D. Goldstein, B. Neale and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data figures and tables

Extended Data Figure 1 Proportion of individuals with a DNM that is probably pathogenic.

Only individuals with protein-altering or protein-truncating DNMs in dominant or X-linked dominant DD-associated genes, or males with DNMs in hemizygous DD-associated genes were included. The proportions given are for those individuals with any DNMs rather than the total number of individuals in each subset. Cohorts included in the DNM meta-analyses are shaded blue.

Extended Data Figure 2 Phenotypic summary of genes without previous compelling evidence.

Phenotypes are grouped by type. The first group indicates numbers of individuals with DNMs per gene divided by sex (m, male; f, female), and by functional consequence (NSV, nonsynonymous variant; PTV, protein-truncating variant). The second group indicates mean values for growth parameters: birthweight (bw), height (ht), weight (wt) and occipitofrontal circumference (OFC). Values are given as standard deviations from the healthy population mean derived from ALSPAC (Avon longitudinal study of parents and children) data. The third group indicates the mean age for achieving developmental milestones: age of first social smile, age of first sitting unassisted, age of first walking unassisted and age of first speaking. Values are given in months. The final group summarizes HPO-coded phenotypes per gene, as number of HPO terms within different clinical categories.

Extended Data Figure 3 Phenotypic summary of individuals with DNMs in genes achieving genome-wide significance.

Phenotypes are grouped by type. The first group indicates numbers of individuals with DNMs per gene divided by sex (m, male; f, female), and by functional consequence (NSV, nonsynonymous variant; PTV, protein-truncating variant). The second group indicates mean values for growth parameters: birthweight (bw), height (ht), weight (wt) and occipitofrontal circumference (OFC). Values are given as standard deviations from the healthy population mean derived from ALSPAC data. The third group indicates the mean age for achieving developmental milestones: age of first social smile, age of first sitting unassisted, age of first walking unassisted and age of first speaking. Values are given in months. The final group summarizes HPO-coded phenotypes per gene, as number of HPO terms within different clinical categories.

Extended Data Figure 4 Dispersion of DNMs and domains for each novel gene.

a, CDK13. b, CHD4. c, CNOT3. d, CSNK2A1. e, GNAI1. f, KCNQ3. g, MSL3. h, PPM1D. i, PUF60. j, QRICH1. k, SET. l, KMT5B. m, TCF20. n, ZBTB18.

Extended Data Figure 5 Effect of clustering by phenotype on the ability to identify genome-wide significant genes.

a, Comparison of P values derived from genotypic information alone versus P values that incorporate genotypic information and phenotypic similarity. b, Comparison of P values from tests in the complete DDD cohort versus tests in the subset with seizures. Genes that were previously linked to seizures are shaded blue. c, Proportion of cohort with a DNM in a seizure-associated gene, stratified by seizure-affected status. Error bars, 95% CI. d, Comparison of power to identify genome-wide significant genes in probands with seizures, versus the unstratified cohort, at matched sample sizes.

Extended Data Figure 6 Power of genome versus exome sequencing to discover dominant genes associated with DDs.

a, The number of genes exceeding genome-wide significance was estimated at three different fixed budgets ($USD1, 2 or 3 million) and a range of relative sensitivities for genomes versus exomes to detect DNMs. The number of genes identifiable by exome sequencing are shaded blue, whereas the number of genes identifiable by genome sequencing are shaded green. The regions where exome sequencing costs 30–40% of genome sequencing are shaded with a grey background, which corresponds to the price differential in 2016. b, Simulated estimates of power to detect loss-of-function genes in the genome at different cohort sizes, given fixed budgets.

Extended Data Figure 7 Gene-wise significance of neurodevelopmental genes versus the expected number of mutations per gene.

Points are shaded by clinical recognizability classification (blue and brown points denote cryptic and distinctive disorders, respectively). Genes have been separated into two plots. Left, genes for cryptic disorders with low, mild or moderate clinical recognizability. Right, genes for distinctive disorders with high clinical recognizability.

Extended Data Figure 8 Stringency of DNM filtering.

a, Sensitivity and specificity of DNM validations within sets filtered using varying thresholds of DNM quality (posterior probability of DNM). The analysed DNMs were restricted to sites identified within the earlier 1,133 trios15, where all candidate DNMs underwent validation experiments. The labelled value is the quality threshold at which the number of candidate synonymous DNMs equals the number of expected synonymous mutations under a null germline mutation rate. b, Excess of missense and loss-of-function DNMs at varying DNM quality thresholds. The DNM excess is adjusted for the sensitivity and specificity at each threshold.

Extended Data Figure 9 Enrichment of DNMs by consequence type, across functional constraint quantiles for residual variation intolerance scores.

A comparison of enrichment for residual variation intolerance score (RVIS) values generated from ESP6500 data (ref. 31) versus ExAC data (obtained from are provided.

Extended Data Table 1 Phenotypes tested for association with having a pathogenic DNM

Supplementary information

Supplementary Information

This file contains a Supplementary Note and the Phenicons for the 94 genes exceeding genome-wide significance (see page 2 for details). (PDF 4196 kb)

Supplementary Tables

This file contains Supplementary Tables 1-4 comprising: (1) de novo mutations (DNM) in the 4,293 DDD individuals. It includes sex, chromosome, position, reference and alternate alleles, HGNC symbol, VEP consequence, posterior probability of DNM and validation status where available. Individual IDs are available on request. This list excludes the sites that failed validations, but includes sites that passed validation (confirmed), sites that were uncertain (uncertain), and sites that were not tested by secondary validation (NA). Genome positions are given as GRCh37 coordinates; (2) Details of cohorts used in meta-analyses. This includes numbers of individuals by sex and publication details; (3) Genes with genome-wide significant statistical evidence to be developmental disorder genes. The numbers of unrelated individuals with independent de novo mutations (DNMs) are given for protein truncating variants (PTV) and missense variants. If any additional individuals were in other cohorts, that number is given in brackets. The P-value reported is the minimum P-value from the testing of the DDD dataset or the meta-analysis dataset. The subset providing the P-value is also listed. Mutations are considered clustered if the P-value proximity clustering of DNMs is less than 0.01; (4) Comparison of known haploinsufficient (HI) neurodevelopment genes to HI and non-HI enrichment models. Genes are ranked by difference in the Akaike’s Information Criterion computed for models where the genes match either expected non-HI PTV enrichment (model 1), or expected HI protein-truncating variant (PTV) enrichment (model 2). (XLSX 629 kb)

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Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature 542, 433–438 (2017).

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