A framework for the interpretation of de novo mutation in human disease

Spontaneously arising (de novo) mutations have an important role in medical genetics. For diseases with extensive locus heterogeneity, such as autism spectrum disorders (ASDs), the signal from de novo mutations is distributed across many genes, making it difficult to distinguish disease-relevant mutations from background variation. Here we provide a statistical framework for the analysis of excesses in de novo mutation per gene and gene set by calibrating a model of de novo mutation. We applied this framework to de novo mutations collected from 1,078 ASD family trios, and, whereas we affirmed a significant role for loss-of-function mutations, we found no excess of de novo loss-of-function mutations in cases with IQ above 100, suggesting that the role of de novo mutations in ASDs might reside in fundamental neurodevelopmental processes. We also used our model to identify ∼1,000 genes that are significantly lacking in functional coding variation in non-ASD samples and are enriched for de novo loss-of-function mutations identified in ASD cases.

• Publication year

  2014

• Venue

  Nature Genetics

• Publication date

  2014-08-03

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/ng.3050PMID 25086666PMCID 4222185
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• De novo mutations in the classic epileptic encephalopathies

  2013cited by this paper
• De novo mutations in epileptic encephalopathies

  2013cited by this paper
• Genic Intolerance to Functional Variation and the Interpretation of Personal Genomes

  2013cited by this paper
• De novo mutations revealed by whole-exome sequencing are strongly associated with autism

  2012cited by this paper
• Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

  2012cited by this paper
• Patterns and rates of exonic de novo mutations in autism spectrum disorders

  2012cited by this paper
• Differential relationship of DNA replication timing to different forms of human mutation and variation.

  2012cited by this paper
• Estimating human mutation rate using autozygosity in a founder population

  2012cited by this paper
• Diagnostic exome sequencing in persons with severe intellectual disability.

  2012cited by this paper
• De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia

  2012cited by this paper
• De novo gene disruptions in children on the autistic spectrum.

  2012cited by this paper
• Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders

  2012cited by this paper
• Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.

  2012cited by this paper
• Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting.

  2011cited by this paper
• Variation in genome-wide mutation rates within and between human families

  2011cited by this paper
• A framework for variation discovery and genotyping using next-generation DNA sequencing data

  2011cited by this paper
• FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism.

  2011cited by this paper
• Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

  2011cited by this paper
• Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism.

  2011cited by this paper
• Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome

  2010cited by this paper
• The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.

  2010cited by this paper
• Fast and accurate long-read alignment with Burrows–Wheeler transform

  2010cited by this paper
• Human mutation rate associated with DNA replication timing

  2009cited by this paper
• Leiter International Performance Scale–Revised

  2008cited by this paper
• Most rare missense alleles are deleterious in humans: implications for complex disease and association studies.

  2007cited by this paper
• Faculty Opinions recommendation of Most rare missense alleles are deleterious in humans: implications for complex disease and association studies.

  2007cited by this paper
• CpG Dinucleotides and Human Disorders

  2006cited by this paper
• Why do human diversity levels vary at a megabase scale?

  2005cited by this paper
• Natural selection on protein-coding genes in the human genome

  2005cited by this paper
• Theoretical and practical advances in genome halving

  2004cited by this paper
• Neighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes.

  1998cited by this paper
• Mullen Scales of Early Learning

  1997cited by this paper
• Adaptive protein evolution at the Adh locus in Drosophila

  1991cited by this paper
• THE PSYCHOLOGICAL CORPORATION.

  1923cited by this paper

• Aberrant mRNA splicing and impaired hippocampal neurogenesis in Grin2b mutant mice

  2026cites this paper
• Fine-tuning protein language models on human spatial constraint improves variant effect prediction by reducing wild-type sequence bias

  2026cites this paper
• Expanding the phenotypic spectrum of MECOM-associated syndrome: rare variants are associated with syndromic pulmonary arterial hypertension

  2026cites this paper
• Inherited burden for disease predisposition in diverse populations.

  2026cites this paper
• Nonlinear transcriptional responses to gradual modulation of transcription factor dosage

  2026influential citation
• CRISPR knockout screens reveal genes and pathways essential for neuronal differentiation and implicate PEDS1 in neurodevelopment.

  2026cites this paper
• Beyond thresholds: a fully Bayesian framework for quantifying allele count evidence for variant pathogenicity

  2026cites this paper
• The Role of de novo and Ultra-Rare Variants in Hirschsprung Disease (HSCR): Extended Gene Discovery for Risk Profiling of Patients

  2025cites this paper
• Rare variants in PRKCI cause Van der Woude syndrome and other features of peridermopathy

  2025cites this paper
• Roadmap to advance therapeutics for SYNGAP1-related disorder: a patient organization perspective from SynGAP Research Fund

  2025cites this paper
• GREGoR: accelerating genomics for rare diseases

  2025cites this paper
• Gene expression patterns of the developing human face at single cell resolution reveal cell type contributions to normal facial variation and disease risk

  2025cites this paper
• Noncoding de novo mutations in SCN2A are associated with autism spectrum disorders

  2025cites this paper
• Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra-rare monogenic presentations

  2025cites this paper
• Analysis of canine gene constraint identifies new variants for orofacial clefts and stature

  2025cites this paper
• Inherited burden for disease predisposition in diverse populations

  2025cites this paper
• HCSeer2: A Deep Learning-Based Multi-Scale Modeling Framework for Predicting Cold and Hot Spots of Variants in the Human Exome

  2025cites this paper
• Elucidating photoreceptor gene function with in-vivo CRISPR knock-out perturbation assay

  2025cites this paper
• A practical framework for predicting splicing single nucleotide variants in exome sequencing

  2025cites this paper
• The impact of ancestral, genetic, and environmental influences on germline de novo mutation rates and spectra

  2025cites this paper
• LIMK1 variants are associated with divergent endocrinological phenotypes and altered exocytosis dynamics

  2025cites this paper
• Rare damaging variants in the sex differences of congenital heart disease: an exome sequencing study

  2025cites this paper
• Trio exome sequencing of an optic nerve hypoplasia cohort reveals evidence for polygenic architecture

  2025cites this paper
• Convergent Evolution and the Epigenome

  2025cites this paper
• Lysine-specific demethylase 1a is obligatory for gene regulation during kidney development

  2025cites this paper
• Genome-wide prediction of dominant and recessive neurodevelopmental disorder-associated genes.

  2025cites this paper
• Common and rare genetic variants show network convergence for a majority of human traits

  2025cites this paper
• Bioinformatics-Driven Multi-Factorial Insight into α-Galactosidase Mutations

  2025cites this paper
• COBT: A gene-based rare variant burden test for case-only study designs using aggregated genotypes from public reference cohorts.

  2025cites this paper
• Cell Cycle Arrest of a ‘Zippering’ Epithelial Cell Cluster Shapes the Face and is Disrupted in Craniofacial Disorders

  2025cites this paper
• Structural basis of nonmuscle myosin-2 autoinhibition mechanisms

  2025cites this paper
• Expanding the utility of variant effect predictions with phenotype-specific models

  2025cites this paper
• Diversity and consequences of structural variation in the human genome

  2025cites this paper
• The spectrum of gene intolerance to variation: Insights from a rare disease cohort

  2025cites this paper
• Functionally constrained human proteins are less prone to mutational instability from single amino acid substitutions

  2025cites this paper
• Distinguishing syndromic and nonsyndromic cleft palate through analysis of protein-altering de novo variants in 816 trios

  2025cites this paper
• Large-scale discovery of neural enhancers for cis-regulation therapies

  2025influential citation
• Actomyosin contractility and a threshold of cadherin cell adhesion are required during tissue fusion

  2025cites this paper
• Benchmarking of variant pathogenicity prediction methods using a population genetics approach

  2025cites this paper
• Long-read proteogenomic atlas of human neuronal differentiation reveals isoform diversity informing neurodevelopmental risk mechanisms

  2025cites this paper
• Investigating the interplay between prematurity and genetic variation in the context of rare developmental disorders

  2025cites this paper
• Systematic phenotype and genotype characterization of Moebius syndrome

  2025cites this paper
• Distinguishing syndromic and nonsyndromic cleft palate through analysis of protein-altering de novo variants in 818 trios

  2025cites this paper
• Unique Signatures of Highly Constrained Genes Across Publicly Available Genomic Databases.

  2025cites this paper
• Meta-analysis reveals transcription factors and DNA binding domain variants associated with congenital heart defect and orofacial cleft

  2025influential citation
• Estimating mutation rate and characterising single nucleotide de novo mutations in pigs

  2025cites this paper
• Germline mosaicism in TCF20-associated neurodevelopmental disorders: a case study and literature review

  2025cites this paper
• Genotype–Phenotype Associations in Phelan–McDermid Syndrome: Insights into Novel Genes Beyond SHANK3

  2025influential citation
• Genetic Investigation of Inherited Variants in a Multiplex Autism Spectrum Disorder (ASD) Family Using Whole-Genome Sequencing (WGS)

  2025cites this paper
• Gene4Denovo2: an updated platform for human de novo mutations discovery and interpretation

  2025cites this paper
• Haploinsufficiency of GRHL2 is associated with orofacial clefting in humans

  2025cites this paper
• Paternal age, de novo mutation, and age at onset among co-affected schizophrenia sib-pairs: whole-genome sequencing in multiplex families

  2025cites this paper
• A novel frameshift variant in the MED13 gene causing intellectual developmental disorder-61 in a Chinese family

  2025cites this paper
• Recessive genetic contribution to congenital heart disease in 5,424 probands

  2025cites this paper
• Integrating gene mutation spectra from tumors and the general population with gene expression topological networks to identify novel cancer driver genes

  2025cites this paper
• Transcriptomic signatures of rare variant impacts across sex and the X chromosome

  2025cites this paper
• Insights from human NF-κB knockouts

  2025cites this paper
• Imputation of fluid intelligence scores reduces ascertainment bias and increases power for analyses of common and rare variants

  2025influential citation
• Exome sequencing of patients with syndromic tall stature reveals four novel candidate genes

  2025cites this paper
• Training Flexible Models of Genetic Variant Effects from Functional Annotations using Accelerated Linear Algebra

  2025cites this paper
• Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome

  2025cites this paper
• Whole-exome sequencing analysis identifies risk genes for schizophrenia

  2025cites this paper
• The oligogenic inheritance test GCOD detects risk genes and their interactions in congenital heart defects

  2025cites this paper
• Diverse ancestral representation improves genetic intolerance metrics

  2025influential citation
• Rare variants in PRKCI cause Van der Woude syndrome and other features of peridermopathy.

  2025cites this paper
• Analyzing the large and complex SFARI autism cohort data using the Genotypes and Phenotypes in Families (GPF) platform

  2025cites this paper
• Genetic variation and molecular profiling of congenital malformations of the female genital tract based on whole-genome sequencing

  2024cites this paper
• Whole-genome sequencing identifies novel genes for autism in Chinese trios

  2024cites this paper
• The role of DEAD- and DExH-box RNA helicases in neurodevelopmental disorders

  2024influential citation
• Functional analysis of ESRP1/2 gene variants and CTNND1 isoforms in orofacial cleft pathogenesis

  2024cites this paper
• Reference-informed prediction of alternative splicing and splicing-altering mutations from sequences

  2024cites this paper
• Neuropathologically directed profiling of PRNP somatic and germline variants in sporadic human prion disease

  2024cites this paper
• Low-level brain somatic mutations in exonic regions are collectively implicated in autism with germline mutations in autism risk genes

  2024cites this paper
• Context-adjusted proportion of singletons (CAPS): a novel metric for assessing negative selection in the human genome

  2024cites this paper
• Functionally constrained human proteins are less prone to mutational instability caused by single amino acid substitutions

  2024cites this paper
• Genetic constraint at single amino acid resolution in protein domains improves missense variant prioritisation and gene discovery

  2024influential citation
• Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.

  2024cites this paper
• Large-scale genomic analysis of the domestic dog informs biological discovery

  2024cites this paper
• Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings

  2024cites this paper
• Functional analysis of ESRP1/2 gene variants and CTNND1 isoforms in orofacial cleft pathogenesis

  2024cites this paper
• Unique Signatures of Highly Constrained Genes Across Publicly Available Genomic Databases

  2024cites this paper
• Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants.

  2024cites this paper
• Dominant Missense Variants in SREBF2 are Associated with Complex Dermatological, Neurological, and Skeletal Abnormalities.

  2024cites this paper
• The phenotypic spectrum of PTCD3 deficiency

  2024cites this paper
• Noncoding de novo mutations in SCN2A are associated with autism spectrum disorders

  2024cites this paper
• Regulatory elements in SEM1-DLX5-DLX6 (7q21.3) locus contribute to genetic control of coronal nonsyndromic craniosynostosis and bone density-related traits

  2024cites this paper
• Essentiality, protein–protein interactions and evolutionary properties are key predictors for identifying cancer-associated genes using machine learning

  2024cites this paper
• Graph Node Classification to Predict Autism Risk in Genes

  2024cites this paper
• The impact of ancestral, environmental and genetic influences on germline de novo mutation rates and spectra

  2024cites this paper
• A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3.

  2024influential citation
• Phenotypic and ancestry-related assortative mating in autism

  2024cites this paper
• The landscape of regional missense mutational intolerance quantified from 125,748 exomes

  2024cites this paper
• Neurodevelopmental Genetic Associations Across the Translational Space-Time Continuum.

  2024cites this paper
• Conserved molecular recognition by an intrinsically disordered region in the absence of sequence conservation

  2024cites this paper
• Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders

  2024cites this paper
• Statistical methods for assessing the effects of de novo variants on birth defects

  2024cites this paper
• AXIN1 mutations in nonsyndromic craniosynostosis.

  2024cites this paper
• Neuropathologically-directed profiling of PRNP somatic and germline variants in sporadic human prion disease

  2024cites this paper
• Bayesian estimation of gene constraint from an evolutionary model with gene features

  2024cites this paper
• Functional neurogenomics in autism spectrum disorders: A decade of progress.

  2024cites this paper