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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    • "The rationale for the present study is that, like other complex traits such as height (Wood et al., 2014) and body mass index (Locke et al., 2015), mutations that result in large deleterious effects in a trait can occur in the same genes underlying the normal variation of a trait. To date many genes have been associated with intellectual disability (de Ligt et al., 2012;Ellison, Rosenfeld, & Shaffer, 2013;Veltman & Brunner, 2012) providing a number of candidate genes for analysis. In the case of intelligence, we exploit the existing knowledge of nonsyndromic autosomal recessive intellectual disabilities (NS-ARID) (Musante & Ropers, 2014) to examine if these same genes are enriched for quantitative trait loci (QTL) associated with variation in the normal range of intelligence differences. "
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    ABSTRACT: Two themes are emerging regarding the molecular genetic aetiology of intelligence. The first is that intelligence is influenced by many variants and those that are tagged by common single nucleotide polymorphisms account for around 30% of the phenotypic variation. The second, in line with other polygenic traits such as height and schizophrenia, is that these variants are not randomly distributed across the genome but cluster in genes that work together. Less clear is whether the very low range of cognitive ability (intellectual disability) is simply one end of the normal distribution describing individual differences in cognitive ability across a population. Here, we examined 40 genes with a known association with non-syndromic autosomal recessive intellectual disability (NS-ARID) to determine if they are enriched for common variants associated with the normal range of intelligence differences. The current study used the 3511 individuals of the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium. In addition, a text mining analysis was used to identify gene sets biologically related to the NS-ARID set. Gene-based tests indicated that genes implicated in NS-ARID were not significantly enriched for quantitative trait loci (QTL) associated with intelligence. These findings suggest that genes in which mutations can have a large and deleterious effect on intelligence are not associated with variation across the range of intelligence differences.
    Full-text · Article · Feb 2016 · Intelligence
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    • "It was hypothesized that such families would likely be enriched for de novo mutations related to the condition, thereby allowing the identification of novel genetic events with major biologic effect in an unbiased genomwide fashion. These initial studies demonstrated the feasibility of obtaining exome data of sufficient quality across the trios (>90% jointly covered) and filtering strategies to identify the ∼1 true de novo event expected per generation (Veltman and Brunner, 2012). Moreover, they appeared to yield a large number of possible candidate genes for these conditions. "
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    ABSTRACT: Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder with a strong but complex genetic component. Recent family based exome-sequencing strategies have identified recurrent de novo mutations at specific genes, providing strong evidence for ASD risk, but also highlighting the extreme genetic heterogeneity of the disorder. However, disruptions in these genes converge on key molecular pathways early in development. In particular, functional enrichment analyses have found that there is a bias toward genes involved in transcriptional regulation, such as chromatin modifiers. Here we review recent genetic, animal model, co-expression network, and functional genomics studies relating to the high confidence ASD risk gene, CHD8. CHD8, a chromatin remodeling factor, may serve as a "master regulator" of a common ASD etiology. Individuals with a CHD8 mutation show an ASD subtype that includes similar physical characteristics, such as macrocephaly and prolonged GI problems including recurrent constipation. Similarly, animal models of CHD8 disruption exhibit enlarged head circumference and reduced gut motility phenotypes. Systems biology approaches suggest CHD8 and other candidate ASD risk genes are enriched during mid-fetal development, which may represent a critical time window in ASD etiology. Transcription and CHD8 binding site profiles from cell and primary tissue models of early development indicate that CHD8 may also positively regulate other candidate ASD risk genes through both direct and indirect means. However, continued study is needed to elucidate the mechanism of regulation as well as identify which CHD8 targets are most relevant to ASD risk. Overall, these initial studies suggest the potential for common ASD etiologies and the development of personalized treatments in the future.
    Full-text · Article · Dec 2015 · Frontiers in Neuroscience
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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). "

    Full-text · Article · Oct 2015
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