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: 36.98). 07/2012; 13(8):565-75. DOI: 10.1038/nrg3241
Source: PubMed


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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    • "to account for ∼10% of males with ID (Ropers 2010) and associated with more than 100 X-linked genes (Musante and Ropers 2014). Autosomal-dominant de novo mutations have been found as an important cause of ID in sporadic patients and have a low recurrence risk (Veltman and Brunner 2012), whereas the role of inherited variants in unaffected parents is less well understood. However, autosomal-recessive ID has a high recurrence risk and is the most common type of ID in consanguineous families (Musante and Ropers 2014), although only approximately 30 loci and 10 genes have been identified to date (Afroze and Chaudhry 2013). "

    10/2015; 1(1):a000562. DOI:10.1101/mcs.a000562
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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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    ABSTRACT: The majority of children with Dravet syndrome (DS) are caused by de novo SCN1A mutations. To investigate the origin of the mutations, we developed and applied a new method that combined deep amplicon re-sequencing with a Bayesian model to detect and quantify allelic fractions with improved sensitivity. Of 174 SCN1A mutations in DS probands which were considered "de novo" by Sanger sequencing, we identified 15 cases (8.6%) of parental mosaicism. We identified another five cases of parental mosaicism that were also detectable by Sanger sequencing. Fraction of mutant alleles in the 20 cases of parental mosaicism ranged from 1.1% to 32.6%. Thirteen (65% of 20) mutations originated paternally and seven (35% of 20) maternally. Twelve (60% of 20) mosaic parents did not have any epileptic symptoms. Their mutant allelic fractions were significantly lower than those in mosaic parents with epileptic symptoms (p = 0.016). We identified mosaicism with varied allelic fractions in blood, saliva, urine, hair follicle, oral epithelium, and semen, demonstrating that postzygotic mutations could affect multiple somatic cells as well as germ cells. Our results suggest that more sensitive tools for detecting low-level mosaicism in parents of families with seemingly "de novo" mutations will allow for better informed genetic counseling. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Human Mutation 06/2015; 36(9). DOI:10.1002/humu.22819 · 5.14 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 . "
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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; · 9.20 Impact Factor
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