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: 29.65). 11/2010; 42(12):1109-12. DOI: 10.1038/ng.712
Source: PubMed

ABSTRACT 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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    • "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 ex- tremity-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 prefer- entially 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.
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    • "One cause of malfunction, genetic mutation, has been associated with several mental illnesses. An increased mutation rate, for example caused by maternal famine (McClellan et al., 2006) or greater paternal age (Crow, 2003; Kong et al., 2012; Sipos et al., 2004), has been associated with increased risk of schizophrenia (Ionita-Laza et al., 2014; Rees et al., 2012; Xu et al., 2008), autism (Durkin et al., 2008; O'Roak et al., 2012; Reichenberg et al., 2006), other developmental disorders (Vissers et al., 2010), and bipolar disorder (Frans et al., 2008). While many studies have identified alleles associated with depression, to our knowledge no study has shown an association between increased mutation rate and MDD. "
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    ABSTRACT: Major depressive disorder (MDD) presents with a variety of symptoms and responds to a wide range of treatment interventions. Diagnostic criteria collapse multiple syndromes with distinct etiologies into the same disorder. MDD is typically understood as a malfunction of neurotransmission or brain circuitry regulating mood, pleasure and reward, or executive function. However, research from an evolutionary perspective suggests that the “normal” functioning of adaptations may also generate symptoms meeting diagnostic criteria. Functioning adaptations may be an underappreciated etiological pathway to MDD. Many adaptive functions for depressive symptoms have been suggested: biasing cognition to avoid losses, conserving energy, disengaging from unobtainable goals, signaling submission, soliciting resources, and promoting analytical thinking. We review the potential role of these adaptive functions and how they can lead to specific clusters of depressive symptoms. Understanding MDD from such a perspective reduces the heterogeneity of cases and may help to select the best intervention for each patient. We discuss the implications of different adaptive and maladaptive etiological pathways for the use of antidepressants and various modes of psychotherapy. In particular, instances of MDD caused by functioning adaptations may benefit most from treatments that support the adaptive function, or that target the precipitating causal stressor. We conclude that an evolutionary approach to the study of MDD may be one of the more promising approaches to reduce its heterogeneity and to better match patients and treatment.
    Journal of Affective Disorders 09/2014; 172. DOI:10.1016/j.jad.2014.09.032 · 3.71 Impact Factor
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    • "This approach was inspired by the successful introduction of WES to identify genetic causes of neurodevelopmental disorders [Veltman and Brunner, 2012]. After a proof of principle study comparing the exomes of a pilot cohort of 10 ID patients with those of the parents, likely causative mutations were identified in six cases [Vissers et al., 2010]. Subsequent studies using the same so called trio approach in larger cohorts of up to 250 patients showed a diagnostic yield in the range of up to 50% [de Ligt et al., 2012; Rauch et al., 2012; Yang et al., 2013]. "
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    ABSTRACT: Mutations in ADNP were recently identified as a frequent cause of syndromic autism, characterized by deficits in social communication and interaction and restricted, repetitive behavioral patterns. Based on its functional domains, ADNP is a presumed transcription factor. The gene interacts closely with the SWI/SNF complex by direct and experimentally verified binding of its C-terminus to three of its core components. A detailed and systematic clinical assessment of the symptoms observed in our patients allows a detailed comparison with the symptoms observed in other SWI/SNF disorders. While the mutational mechanism of the first 10 patients identified suggested a gain of function mechanism, an 11th patient reported here is predicted haploinsufficient. The latter observation may raise hope for therapy, as addition of NAP, a neuroprotective octapeptide named after the first three amino acids of the sequence NAPVSPIQ, has been reported by others to ameliorate some of the cognitive abnormalities observed in a knockout mouse model. It is concluded that detailed clinical and molecular studies on larger cohorts of patients are necessary to establish a better insight in the genotype phenotype correlation and in the mutational mechanism. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 09/2014; 166(3). DOI:10.1002/ajmg.c.31413 · 3.54 Impact Factor
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