A de novo paradigm for mental retardation

Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Nature Genetics (Impact Factor: 29.35). 11/2010; 42(12):1109-12. DOI: 10.1038/ng.712
Source: PubMed


The per-generation mutation rate in humans is high. De novo mutations may compensate for allele loss due to severely reduced fecundity in common neurodevelopmental and psychiatric diseases, explaining a major paradox in evolutionary genetic theory. Here we used a family based exome sequencing approach to test this de novo mutation hypothesis in ten individuals with unexplained mental retardation. We identified and validated unique non-synonymous de novo mutations in nine genes. Six of these, identified in six different individuals, are likely to be pathogenic based on gene function, evolutionary conservation and mutation impact. Our findings provide strong experimental support for a de novo paradigm for mental retardation. Together with de novo copy number variation, de novo point mutations of large effect could explain the majority of all mental retardation cases in the population.

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    • ". Mutations of the RAB39B gene associated with X-linked intellectual disability (Andersen et al., 2014; Giannandrea et al., 2010; Vissers et al., 2010; Wilson et al., 2014). Asterisks designate mutations identified in patients with X-linked intellectual disability and Parkinson's disease. "

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    • "As an example, YY1 is known to interact directly with HCFC1 [Jolly et al., 2015] and MECP2 [Forlani et al., 2010]: YY1 and MECP2 cooperate in repressing the mitochondrial adenine translocase ANT1, which is overexpressed in neurologically impaired mice lacking Mecp2 and in fibroblasts of patients with Rett syndrome. A de novo YY1 missense variant was reported in a patient with ID [Vissers et al., 2010]. This model is further supported by the comparison of patients with TS caused by different mechanisms (UPD and epigenetic aberrations ): less than 50% (11/26) of patients with UPD(14) mat are reported to have ID [Ioannides et al., 2014]. "
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    ABSTRACT: Temple syndrome (TS) is caused by abnormal expression of genes at the imprinted locus 14q32. A subset of TS patients carry 14q32 deletions of paternal origin. We aimed to define possible genotype-phenotype correlations and to highlight the prevalence of thyroid dysfunction, which is a previously unreported feature of TS. We described four new patients who carry deletions of paternal origin at 14q32 detected by array-CGH and reviewed nine patients reported in the medical literature. We compared clinical features with respect to deletion size and position. Expression of DLK1 is altered in all the patients with TS, but intellectual disability (ID) is present only in patients with larger deletions extending proximally to the imprinted locus. This study led to the identification of an ID "critical region" containing four annotated genes including YY1 as the strongest candidate. Furthermore, we described three patients with thyroid dysfunction, which progressed to papillary carcinoma at a very young age in two of them. We conclude that DLK1 loss of function is likely to be responsible for the core features of TS, while haploinsufficiency of a gene outside the imprinted region causes ID. Thyroid cancer may be an unrecognized feature and monitoring for thyroid dysfunction should thus be considered in TS patients. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2015; DOI:10.1002/ajmg.a.37346 · 2.16 Impact Factor
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    • "by guest on December 25, 2014 Downloaded from atrophy, lower extremity predominant features (including 10/11 affected members of Family 3), all of whom had proximal lower limb involvement, with or without additional distal involvement. No cohort members had a history of epilepsy in contrast to patients with spinal muscular atrophy, lower extremity predominant due to mutations in DYNC1H1, where epilepsy may be a common additional feature (Vissers et al., 2010; Willemsen et al., 2012; Poirier et al., 2013; Fiorillo et al., 2014). In addition, none of the seven cohort members from Families 3, 4, 6 and 7 who underwent brain MRI nor the one patient from Family 1 at post-mortem, had evidence of malformations of cortical development. "
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    ABSTRACT: Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower extremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein-dynactin complex and one of its cargo adaptors, BICD2. We have now identified 32 patients with BICD2 mutations from nine different families, providing detailed insights into the clinical phenotype and natural history of BICD2 disease. BICD2 spinal muscular atrophy, lower extremity predominant most commonly presents with delayed motor milestones and ankle contractures. Additional features at presentation include arthrogryposis and congenital dislocation of the hips. In all affected individuals, weakness and wasting is lower-limb predominant, and typically involves both proximal and distal muscle groups. There is no evidence of sensory nerve involvement. Upper motor neuron signs are a prominent feature in a subset of individuals, including one family with exclusively adult-onset upper motor neuron features, consistent with a diagnosis of hereditary spastic paraplegia. In all cohort members, lower motor neuron features were static or only slowly progressive, and the majority remained ambulant throughout life. Muscle MRI in six individuals showed a common pattern of muscle involvement with fat deposition in most thigh muscles, but sparing of the adductors and semitendinosus. Muscle pathology findings were highly variable and included pseudomyopathic features, neuropathic features, and minimal change. The six causative mutations, including one not previously reported, result in amino acid changes within all three coiled-coil domains of the BICD2 protein, and include a possible 'hot spot' mutation, p.Ser107Leu present in four families. We used the recently solved crystal structure of a highly conserved region of the Drosophila orthologue of BICD2 to further-explore how the p.Glu774Gly substitution inhibits the binding of BICD2 to Rab6. Overall, the features of BICD2 spinal muscular atrophy, lower extremity predominant are consistent with a pathological process that preferentially affects lumbar lower motor neurons, with or without additional upper motor neuron involvement. Defining the phenotypic features in this, the largest BICD2 disease cohort reported to date, will facilitate focused genetic testing and filtering of next generation sequencing-derived variants in cases with similar features. © 2014 The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected] /* */
    Brain 02/2015; DOI:10.1093/brain/awu356 · 9.20 Impact Factor
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