Key Points
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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.
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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.
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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.
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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).
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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.
Abstract
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.
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Acknowledgements
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).
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NRG article series on the Applications of Next-Generation Sequencing
Glossary
- 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.
- Indels
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Small insertions or deletions of 1–1,000 nucleotides.
- Copy number variants
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Large insertions or deletions of more than 1,000 nucleotides.
- Schinzel–Giedion syndrome
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A rare genetic disorder that is characterized by congenital hydronephrosis, skeletal dysplasia and severe developmental retardation.
- Kabuki syndrome
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A rare genetic condition that is characterized by distinctive facial features, skeletal abnormalities and intellectual disabilities.
- Bohring–Opitz syndrome
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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.
- Achondroplasia
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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.
- Penetrance
-
The proportion of patients with a specific phenotype among all carriers of a specific genotype.
- Expressivity
-
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.
- Adrenoleukodystrophy
-
A rare genetic disorder that results in progressive brain damage, failure of adrenal glands and, eventually, death.
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Veltman, J., Brunner, H. De novo mutations in human genetic disease. Nat Rev Genet 13, 565–575 (2012). https://doi.org/10.1038/nrg3241
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DOI: https://doi.org/10.1038/nrg3241
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