Traditional genetic approaches such as linkage analysis and genome-wide association studies are focused on inherited genetic variation. Unbiased whole-genome and whole-exome sequencing now, for the first time, allows us to study the role of de novo mutations in health and disease.
Each generation (per individual), approximately 74 de novo single-nucleotide variants (SNVs), three novel indels (small insertions or deletions) and 0.02 larger copy number variants (CNVs) arise in our genome. Risk factors that increase this de novo mutation rate include advanced paternal age at conception, a local genomic architecture that is full of segmental duplications, and genetic variation that is yet to be discovered.
Exome sequencing has recently revealed disruptive de novo mutations in one or two genes as the major cause of many rare genetic syndromes, such as Kabuki, Schinzel–Giedion, Bohring–Opitz, Baraitser–Winter and Coffin–Siris syndromes.
De novo mutations can also play a major part in common diseases such as intellectual disability, autism and schizophrenia, which are all associated with reduced fitness and have a large mutational target (that is, a large number of genes or non-genic elements that cause the disease when mutated).
Predicting the pathogenicity of rare de novo missense mutations in novel genes is particularly challenging. However, it is greatly facilitated by the identification of recurrent mutations in patients with similar phenotypes, allowing detailed genotype–phenotype studies to be carried out. The identification of these mutations requires international collaboration, as the recurrent mutations will be rare for genetically heterogeneous diseases.
New mutations have long been known to cause genetic disease, but their true contribution to the disease burden can only now be determined using family-based whole-genome or whole-exome sequencing approaches. In this Review we discuss recent findings suggesting that de novo mutations play a prominent part in rare and common forms of neurodevelopmental diseases, including intellectual disability, autism and schizophrenia. De novo mutations provide a mechanism by which early-onset reproductively lethal diseases remain frequent in the population. These mutations, although individually rare, may capture a significant part of the heritability for complex genetic diseases that is not detectable by genome-wide association studies.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Raychaudhuri, S. Mapping rare and common causal alleles for complex human diseases. Cell 147, 57–69 (2011).
Conrad, D. F. et al. Variation in genome-wide mutation rates within and between human families. Nature Genet. 43, 712–714 (2011).
Vogel, F. & Rathenberg, R. Spontaneous mutation in man. Adv. Hum. Genet. 5, 223–318 (1975).
Kondrashov, A. S. Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases. Hum. Mutat. 21, 12–27 (2002). These authors accurately estimate the de novo mutation rate of SNVs long before the availability of whole-genome and whole-exome sequencing technologies.
Crow, J. F. The origins, patterns and implications of human spontaneous mutation. Nature Rev. Genet. 1, 40–47 (2000).
Eyre-Walker, A. & Keightley, P. D. The distribution of fitness effects of new mutations. Nature Rev. Genet. 8, 610–618 (2007).
Hoischen, A. et al. De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nature Genet. 42, 483–485 (2010). The first demonstration of exome sequencing being used to identify de novo mutations in a rare clinical syndrome.
Ng, S. B. et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nature Genet. 42, 790–793 (2010).
Hoischen, A. et al. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. Nature Genet. 43, 729–731 (2011).
Lindhurst, M. J. et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N. Engl. J. Med. 365, 611–619 (2011). The first application of exome sequencing to discover somatic de novo mutations as the cause of a genetic disorder.
Vissers, L. E. L. M. et al. A de novo paradigm for mental retardation. Nature Genet. 42, 1109–1112 (2010). The first study to use exome sequencing of patient–parent trios to identify de novo mutations in a complex trait that is characterized by extreme genetic heterogeneity.
O'Roak, B. J. et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nature Genet. 43, 585–589 (2011).
Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012).
Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012).
O'Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012).
Iossifov, I. et al. De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285–299 (2012). The largest-scale exome sequencing study carried out to date. The authors study 343 quartets, each consisting of a patient with an ASD, an unaffected sibling and their unaffected parents, to evaluate the frequency and type of de novo mutations in affected and unaffected siblings.
Girard, S. L. et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nature Genet. 43, 860–863 (2011).
Xu, B. et al. Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nature Genet. 43, 864–868 (2011).
McClellan, J. & King, M. C. Genetic heterogeneity in human disease. Cell 141, 210–217 (2010).
McClellan, J. & King, M. C. Genomic analysis of mental illness: a changing landscape. JAMA 303, 2523–2524 (2010).
Meyerson, M., Gabriel, S. & Getz, G. Advances in understanding cancer genomes through second-generation sequencing. Nature Rev. Genet. 11, 685–696 (2010).
Ding, L., Wendl, M. C., Koboldt, D. C. & Mardis, E. R. Analysis of next-generation genomic data in cancer: accomplishments and challenges. Hum. Mol. Genet. 19, R188–R196 (2010).
Arnheim, N. & Calabrese, P. Understanding what determines the frequency and pattern of human germline mutations. Nature Rev. Genet. 10, 478–488 (2009).
Hodgkinson, A. & Eyre-Walker, A. Variation in the mutation rate across mammalian genomes. Nature Rev. Genet. 12, 756–766 (2011).
Loewe, L. & Hill, W. G. The population genetics of mutations: good, bad and indifferent. Phil. Trans. R. Soc. B. 365, 1153–1167 (2010).
Haldane, J. B. S. The rate of spontaneous mutation of a human gene. J. Genet. 31, 317–326 (1935).
Kondrashov, A. S. & Crow, J. F. A molecular approach to estimating the human deleterious mutation rate. Hum. Mutat. 2, 229–234 (1993).
Roach, J. C. et al. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328, 636–639 (2010). The first family-based whole-genome sequencing study in which all potential de novo mutations are independently validated to provide accurate de novo mutation rates.
Lynch, M. Rate, molecular spectrum, and consequences of human mutation. Proc. Natl Acad. Sci. USA 107, 961–968 (2010).
Itsara, A. et al. De novo rates and selection of large copy number variation. Genome Res. 20, 1469–1481 (2010).
Allen, G. Aetiology of Down's syndrome inferred by Waardenburg in 1932. Nature 250, 436–437 (1974).
Zhang, F., Gu, W., Hurles, M. E. & Lupski, J. R. Copy number variation in human health, disease, and evolution. Annu. Rev. Genomics Hum. Genet. 10, 451–481 (2009).
Girirajan, S., Campbell, C. D. & Eichler, E. E. Human copy number variation and complex genetic disease. Annu. Rev. Genet. 45, 203–226 (2011).
Vissers, L. E. L. M. et al. Mutations in a novel member of the chromodomain gene family cause CHARGE syndrome. Nature Genet. 36, 955–957 (2004).
Bamshad, M. J., et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nature Rev. Genet. 12, 745–755 (2011). A valuable review that explains the experimental and analytical options for applying exome sequencing in studies of disease genes. The key challenges in using this approach are also discussed.
Gilissen, C., Hoischen, A., Brunner, H. G. & Veltman, J. A. Unlocking Mendelian disease using exome sequencing. Genome Biol. 12, 228 (2011).
Sirmaci, A., et al. Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia. Am. J. Hum. Genet. 89, 289–294 (2011).
Rivière, J. B., et al. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nature Genet. 44, 440–444 (2012).
Tsurusaki, Y., et al. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nature Genet. 44, 376–378 (2012).
Santen, G. W., et al. Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Nature Genet. 44, 379–380 (2012).
Pansuriya, T. C., et al. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nature Genet. 43, 1256–1261 (2011).
Vissers, L. E. L. M. et al. Whole-exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA). Am. J. Med. Genet. A 155, 2609–2616 (2011).
Limaye, N., Boon, L. M. & Vikkula, M. From germline towards somatic mutations in the pathophysiology of vascular anomalies. Hum. Mol. Genet. 18, R65–R74 (2009).
Pasmooij, A. M., Pas, H. H., Bolling, M. C. & Jonkman, M. F. Revertant mosaicism in junctional epidermolysis bullosa due to multiple correcting second-site mutations in LAMB3. J. Clin. Invest. 117, 1240–1248 (2007).
Frank, S. A. Somatic evolutionary genomics: mutations during development cause highly variable genetic mosaicism with risk of cancer and neurodegeneration. Proc. Natl Acad. Sci. USA 107 (Suppl. 1), 1725–1730 (2010).
Carlson, C. A. et al. Decoding cell lineage from acquired mutations using arbitrary deep sequencing. Nature Methods 9, 78–80 (2011).
Vanneste, E. et al. Chromosome instability is common in human cleavage-stage embryos. Nature Med. 15, 577–583 (2009). A remarkable study which shows that de novo chromosomal aberrations are common in early embryogenesis. This identifies postzygotic chromosome instability as a major cause of constitutional genomic disorders.
van Echten-Arends, J. et al. Chromosomal mosaicism in human preimplantation embryos: a systematic review. Hum. Reprod. Update 17, 620–627 (2011).
Cook, E. H. Jr & Scherer, S. W. Copy-number variations associated with neuropsychiatric conditions. Nature 455, 919–923 (2008).
Vissers, L. E. L. M., de Vries, B. B. & Veltman, J. A. Genomic microarrays in mental retardation: from CNV to gene, from research to diagnosis. J. Med. Genet. 47, 289–297 (2010).
Koolen, D. A. et al. Genomic microarrays in mental retardation: a practical workflow for diagnostic applications. Hum. Mutat. 30, 283–292 (2009).
Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007). One of the first large-scale studies to highlight the important role of de novo CNVs in sporadic forms of ASDs, establishing de novo germline mutation as a more significant risk factor for ASDs than was previously recognized.
Marshall, C. R. et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477–488 (2008).
Xu, B. et al. Strong association of de novo copy number mutations with sporadic schizophrenia. Nature Genet. 40, 880–885 (2008).
Vermeesch, J. R., Balikova, I., Schrander-Stumpel, C., Fryns, J. P. & Devriendt, K. The causality of de novo copy number variants is overestimated. Eur. J. Hum. Genet. 19, 1112–1113 (2011).
Girirajan, S. et al. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nature Genet. 42, 203–209 (2010).
Hamdan, F. F. et al. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N. Engl. J. Med. 360, 599–605 (2009).
Gauthier, J. et al. De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia. Proc. Natl Acad. Sci. USA 107, 7863–7868 (2010).
Awadalla, P. et al. Direct measure of the de novo mutation rate in autism and schizophrenia cohorts. Am. J. Hum. Genet. 87, 316–324 (2010). These authors carry out the first systematic large-scale sequencing study to evaluate the role of de novo mutations in candidate genes for ASDs and schizophrenia.
Hamdan, F. F. et al. Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am. J. Hum. Genet. 88, 306–316 (2011).
Hultman, C. M. et al. Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Mol. Psychiatry 16, 1203–1212 (2011).
He, Y. & Casaccia-Bonnefil, P. The Yin and Yang of YY1 in the nervous system. J. Neurochem. 106, 1493–1502 (2008).
Webber, C. et al. Forging links between human mental retardation-associated CNVs and mouse gene knockout models. PLoS Genet. 5, e1000531 (2009).
Pinto, D. et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466, 368–372 (2010).
O'Dushlaine, C. et al. Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility. Mol. Psychiatry 16, 286–292 (2011).
Erten, S. et al. DADA: degree-aware algorithms for network-based disease gene prioritization. BioData Min. 4, 19 (2011).
Chen, Y. et al. In silico gene prioritization by integrating multiple data sources. PLoS ONE 6, e21137 (2011).
Pollard, K. S., Hubisz, M. J., Rosenbloom, K. R. & Siepel, A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 20, 110–121 (2010).
Cooper, G. M. et al. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res. 15, 901–913 (2005).
Grantham, R. Amino acid difference formula to help explain protein evolution. Science 185, 862–864 (1974).
Ramensky, V., Bork, P. & Sunyaev, S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 30, 3894–3900 (2002).
Kryukov, G. V., Pennacchio, L. A. & Sunyaev, S. R. Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am. J. Hum. Genet. 80, 727–739 (2007).
Huang, N. et al. Characterising and predicting haploinsufficiency in the human genome. PLoS Genet. 6, e1001154 (2010).
Firth, H. V. et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am. J. Hum. Genet. 84, 524–533 (2009).
Zhang, J. et al. Development of bioinformatics resources for display and analysis of copy number and other structural variants in the human genome. Cytogenet. Genome Res. 115, 205–214 (2006).
Najmabadi, H. et al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478, 57–63 (2011).
Vadlamudi, L. et al. Timing of de novo mutagenesis — a twin study of sodium-channel mutations. N. Engl. J. Med. 363, 1335–1340 (2010).
Aretz, S. et al. Somatic APC mosaicism: a frequent cause of familial adenomatous polyposis (FAP). Hum. Mutat. 10, 985–992 (2007).
Goriely, A. et al. Germline and somatic mosaicism for FGFR2 mutation in the mother of a child with Crouzon syndrome: implications for genetic testing in “paternal age-effect” syndromes. Am. J. Med. Genet. A 152A, 2067–2073 (2010).
Erickson, R. P. Somatic gene mutation and human disease other than cancer: an update. Mutat. Res. 705, 96–106 (2010).
Helderman-van den Enden, A. T. et al. Recurrence risk due to germ line mosaicism: Duchenne and Becker muscular dystrophy. Clin. Genet. 75, 465–472 (2009).
Twigg, S. R. et al. The origin of EFNB1 mutations in craniofrontonasal syndrome: frequent somatic mosaicism and explanation of the paucity of carrier males. Am. J. Hum. Genet. 78, 999–1010 (2006).
Wang, Y. et al. X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism. Mol. Genet. Metab. 104, 160–166 (2011).
Lo, Y. M. Fetal nucleic acids in maternal plasma. Ann. NY Acad. Sci. 1137, 140–143 (2008).
Lo, Y. M. et al. Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Sci. Transl. Med. 2, 61ra91 (2010).
Fragouli, E., Wells, D. & Delhanty, J. D. Chromosome abnormalities in the human oocyte. Cytogenet. Genome Res. 133, 107–118 (2011).
Goriely, A. & Wilkie, A. O. Missing heritability: paternal age effect mutations and selfish spermatogonia. Nature Rev. Genet. 11, 589 (2010).
Goriely, A. & Wilkie, A. O. Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am. J. Hum. Genet. 90, 175–200 (2012).
Toriello, H. V., Meck, J. M. & Professional Practice and Guidelines Committee. Statement on guidance for genetic counseling in advanced paternal age. Genet. Med. 10, 457–460 (2008).
Hehir-Kwa, J. Y. et al. De novo copy number variants associated with intellectual disability have a paternal origin and age bias. J. Med. Genet. 48, 776–778 (2011).
Koolen, D. A. et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nature Genet. 38, 999–1001 (2006).
Sharp, A. J. et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nature Genet. 38, 1038–1042 (2006).
Shaw-Smith, C. et al. Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nature Genet. 38, 1032–1037 (2006).
Koolen, D. A. et al. Clinical and molecular delineation of the 17q21.31 microdeletion syndrome. J. Med. Genet. 45, 710–720 (2008).
Itsara, A. et al. Resolving the breakpoints of the 17q21.31 microdeletion syndrome with next-generation sequencing. Am. J. Hum. Genet. 90, 599–613 (2012).
Stefansson, H. et al. A common inversion under selection in Europeans. Nature Genet. 37, 129–137 (2005).
Baudat, F. et al. PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science 327, 836–840 (2010).
Berg, I. L. et al. Variants of the protein PRDM9 differentially regulate a set of human meiotic recombination hotspots highly active in African populations. Proc. Natl Acad. Sci. USA 108, 12378–12383 (2011).
Berg, I. L. et al. PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans. Nature Genet. 42, 859–863 (2010).
Tomé, S. et al. Maternal germline-specific effect of DNA ligase I on CTG/CAG instability. Hum. Mol. Genet. 20, 2131–2143 (2011).
Liu, P. et al. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements, Cell 146, 889–903 (2011).
Bunyan, D. J. & Robinson, D. O. Multiple de novo mutations in the MECP2 gene. Genet. Test. 12, 373–375 (2008).
Lam, H. Y. et al. Performance comparison of whole-genome sequencing platforms. Nature Biotech. 30, 78–82 (2011).
Londin, E. R. et al. Whole-exome sequencing of DNA from peripheral blood mononuclear cells (PBMC) and EBV-transformed lymphocytes from the same donor. BMC Genomics 12, 464 (2011).
Hussein, S. M. et al. Copy number variation and selection during reprogramming to pluripotency. Nature 471, 58–62 (2011).
Liang, Q., Conte, N., Skarnes, W. C. & Bradley, A. Extensive genomic copy number variation in embryonic stem cells. Proc. Natl Acad. Sci. USA 105, 17453–17456 (2008).
Pamphlett, R., Morahan, J. M. & Yu, B. Using case-parent trios to look for rare de novo genetic variants in adult-onset neurodegenerative diseases. J. Neurosci. Methods 197, 297–301 (2011).
Joris A. Veltman is supported by personal grants from the Netherlands Organization for Health Research and Development (917-66-363) and the European Research Council (281964).
The authors declare no competing financial interests.
- Single-nucleotide variants
Differences in the nucleotide composition at single positions in the DNA sequence. The most common form of variation in the human genome.
Small insertions or deletions of 1–1,000 nucleotides.
- Copy number variants
Large insertions or deletions of more than 1,000 nucleotides.
- Schinzel–Giedion syndrome
A rare genetic disorder that is characterized by congenital hydronephrosis, skeletal dysplasia and severe developmental retardation.
- Kabuki syndrome
A rare genetic condition that is characterized by distinctive facial features, skeletal abnormalities and intellectual disabilities.
- Bohring–Opitz syndrome
A rare genetic disorder that is characterized by facial anomalies, multiple malformations, failure to thrive and severe intellectual disabilities.
- Proteus syndrome
A rare syndrome that is characterized by patchy or mosaic overgrowth and hyperplasia of various tissues and organs.
- CpG sites
Genomic regions of several hundred base pairs with a high GC content and many unmethylated CpG dinucleotides.
- Somatic mosaicism
The presence of mutations in a proportion of the cells in the body but not in sperm and egg cells.
A common form of dwarfism that is inherited in an autosomal dominant manner.
- Apert syndrome
An autosomal dominant disorder that is characterized by premature closing of cranial sutures and by fused fingers and toes.
- Crouzon syndrome
A rare genetic disorder that is characterized by premature fusion of the skull bones (craniosynostosis).
- Multiple endocrine neoplasia type 2
Early-childhood thyroid cancer caused by mutations in the proto-oncogene RET that are inherited in an autosomal dominant manner.
- Charcot–Marie–Tooth disease type 1a
A rare genetic neurological disorder that affects the peripheral nerves.
- CHARGE syndrome
A rare genetic disorder that arises during early fetal development and affects multiple organ systems, such as the eyes, heart and ears.
- KBG syndrome
A rare genetic condition that is characterized by facial dysmorphisms, macrodontia, skeletal anomalies and developmental delay.
- Lymphoblastoid cell lines
Cell lines that are created through in vitro infection (and thus immortalization) of B cells with Epstein–Barr virus.
- Induced pluripotent stem cells
Adult cells that have been reprogrammed to stem cells, which can differentiate into different cell types.
The proportion of patients with a specific phenotype among all carriers of a specific genotype.
The severity of the disease in individuals who have both the risk variant and the disease.
- Genetic heterogeneity
The phenomenon by which mutations in different genes can cause a similar phenotype.
- Purifying selection
The conservation of functional genetic features during evolution because of selection against deleterious mutations.
- Privately inherited
Pertaining to a genetic variant: confined to a single individual, family or population.
- Grantham difference score
A score that predicts the effect of non-synonymous mutations based on the chemical properties of the substituted amino acids.
A rare genetic disorder that results in progressive brain damage, failure of adrenal glands and, eventually, death.
About this article
Cite this article
Veltman, J., Brunner, H. De novo mutations in human genetic disease. Nat Rev Genet 13, 565–575 (2012). https://doi.org/10.1038/nrg3241
International Journal of Molecular Sciences (2021)
First Somatic PRKAR1A Defect Associated With Mosaicism for Another PRKAR1A Mutation in a Patient With Cushing Syndrome
Journal of the Endocrine Society (2021)
Human Genetics (2021)
Frontiers in Cell and Developmental Biology (2021)
European Journal of Human Genetics (2021)