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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    • "Out of these 20 cases of parental mosaicism, 13 (65% of 20) originated from paternal mosaicism and seven (35% of 20) from maternal mosaicism. This was consistent with the predominantly paternal origin of de novo mutations previously reported in Mendelian disorders , complex diseases, and healthy individuals [Kong et al., 2012; Veltman and Brunner, 2012; Ronemus et al., 2014]. PASM detected mutant mosaicism in both the father and mother in Family DS082 (15.5% and 9.4%, respectively, for NM 001165963.1 c.4822G>T). "
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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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    • "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. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.
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