Article

De novo mutations in human genetic disease

Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Institute for Genetic and Metabolic disease, Radboud University Nijmegen Medical Center, PO Box 9101, Nijmegen, The Netherlands.
Nature Reviews Genetics (Impact Factor: 39.79). 07/2012; 13(8):565-75. DOI: 10.1038/nrg3241
Source: PubMed

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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    • "Cerebral palsy is a relatively common disorder, but de novo mutations are rare genetic events. This paradox can be explained by the reciprocal relationship between the size of the 'mutational target' (i.e. the cumulative size of gene loci in which a single large-effect mutation may cause the phenotype) and the frequency of a disease caused by de novo mutations (Veltman and Brunner, 2012). In the case of cerebral palsy the 'mutational target' is likely to include a huge number of neurodevelopmental genes in which individually rare single de novo mutations can lead to an overall high frequency of cerebral palsy within the population . "
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    ABSTRACT: Cerebral palsy is a sporadic disorder with multiple likely aetiologies, but frequently considered to be caused by birth asphyxia. Genetic investigations are rarely performed in patients with cerebral palsy and there is little proven evidence of genetic causes. As part of a large project investigating children with ataxia, we identified four patients in our cohort with a diagnosis of ataxic cerebral palsy. They were investigated using either targeted next generation sequencing or trio-based exome sequencing and were found to have mutations in three different genes, KCNC3, ITPR1 and SPTBN2. All the mutations were de novo and associated with increased paternal age. The mutations were shown to be pathogenic using a combination of bioinformatics analysis and in vitro model systems. This work is the first to report that the ataxic subtype of cerebral palsy can be caused by de novo dominant point mutations, which explains the sporadic nature of these cases. We conclude that at least some subtypes of cerebral palsy may be caused by de novo genetic mutations and patients with a clinical diagnosis of cerebral palsy should be genetically investigated before causation is ascribed to perinatal asphyxia or other aetiologies.
    Brain 05/2015; · 10.23 Impact Factor
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    • "Cerebral palsy is a relatively common disorder, but de novo mutations are rare genetic events. This paradox can be explained by the reciprocal relationship between the size of the 'mutational target' (i.e. the cumulative size of gene loci in which a single large-effect mutation may cause the phenotype) and the frequency of a disease caused by de novo mutations (Veltman and Brunner, 2012). In the case of cerebral palsy the 'mutational target' is likely to include a huge number of neurodevelopmental genes in which individually rare single de novo mutations can lead to an overall high frequency of cerebral palsy within the population . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cerebral palsy is a sporadic disorder with multiple likely aetiologies, but frequently considered to be caused by birth asphyxia. Genetic investigations are rarely performed in patients with cerebral palsy and there is little proven evidence of genetic causes. As part of a large project investigating children with ataxia, we identified four patients in our cohort with a diagnosis of ataxic cerebral palsy. They were investigated using either targeted next generation sequencing or trio-based exome sequencing and were found to have mutations in three different genes, KCNC3, ITPR1 and SPTBN2. All the mutations were de novo and associated with increased paternal age. The mutations were shown to be pathogenic using a combination of bioinformatics analysis and in vitro model systems. This work is the first to report that the ataxic subtype of cerebral palsy can be caused by de novo dominant point mutations, which explains the sporadic nature of these cases. We conclude that at least some subtypes of cerebral palsy may be caused by de novo genetic mutations and patients with a clinical diagnosis of cerebral palsy should be genetically investigated before causation is ascribed to perinatal asphyxia or other aetiologies. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.
    Brain 05/2015; DOI:10.1093/brain/awv117 · 10.23 Impact Factor
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    • "Copy number variations are widely studied and have been implicated in a variety of neurological disorders, such as autism (Sebat et al. 2007), schizophrenia (Walsh et al. 2008), and intellectual disability (Cooper et al. 2011). Recent large-scale exome sequencing studies have uncovered de novo SNVs and short indels causing various disease phenotypes, ranging from complex neurological disease to rare Mendelian disorders (Veltman and Brunner 2012). Given the significant contribution of de novo mutations to human disease and evolution, studying genome-wide mutation rates and patterns is important for understanding mutation origins , locating hotspots, estimating disease risk, and interpreting novel disease-associated mutations. "
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    ABSTRACT: Small insertions and deletions (indels) and large structural variations (SVs) are major contributors to human genetic diversity and disease. However, mutation rates and characteristics of de novo indels and SVs in the general population have remained largely unexplored. We report 332 validated de novo structural changes identified in whole genomes of 250 families, including complex indels, retrotransposon insertions and interchromosomal events. These data indicate a mutation rate of 2.94 indels (1-20bp) and 0.16 SVs (>20bp) per generation. De novo structural changes affect on average 4.1kbp of genomic sequence and 29 coding bases per generation, which is 91 and 52 times more nucleotides than de novo substitutions, respectively. This contrasts with the equal genomic footprint of inherited SVs and substitutions. An excess of structural changes originated on paternal haplotypes. Additionally, we observed a non-uniform distribution of de novo SVs across offspring. These results reveal the importance of different mutational mechanisms to changes in human genome structure across generations. Published by Cold Spring Harbor Laboratory Press.
    Genome Research 04/2015; DOI:10.1101/gr.185041.114 · 13.85 Impact Factor
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