The genetic variability and commonality of neurodevelopmental disease

Department of Genome Sciences and Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA, USA.
American Journal of Medical Genetics Part C Seminars in Medical Genetics (Impact Factor: 3.91). 05/2012; 160C(2):118-29. DOI: 10.1002/ajmg.c.31327
Source: PubMed


Despite detailed clinical definition and refinement of neurodevelopmental disorders and neuropsychiatric conditions, the underlying genetic etiology has proved elusive. Recent genetic studies have revealed some common themes: considerable locus heterogeneity, variable expressivity for the same mutation, and a role for multiple disruptive events in the same individual affecting genes in common pathways. Recurrent copy number variation (CNV), in particular, has emphasized the importance of either de novo or essentially private mutations creating imbalances for multiple genes. CNVs have foreshadowed a model where the distinction between milder neuropsychiatric conditions from those of severe developmental impairment may be a consequence of increased mutational burden affecting more genes.

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    • "recombination events can result in significant duplications or deletions of genomic DNA sequence [Gilbert et al., 2002; Symer et al., 2002; Cordaux et al., 2006; Mine et al., 2006; Takasu et al., 2007; Han et al., 2008] or (6) create microsatellites from homopolymeric genomic tracts. Moreover, Alus and LINEs are key factors in generating Copy Number Variants (for more details on this mechanism see the section of the article " The impact of TEs on the Human Genome and the Central Nervous System (CNS) " [Mills et al., 2006, 2011; Maiti et al., 2011; Coe et al., 2012; Malhotra and Sebat, 2012; Gokcumen et al., 2013]). Schematic representations have been inspired by images in Cordaux and Batzer [2009]. "
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    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2014; 165(3). DOI:10.1002/ajmg.b.32225 · 3.42 Impact Factor
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    • "ASDs are currently estimated to affect ~1% of children ( Autism and Develop - mental Disabilities Monitoring Network 2009 ) and significantly skewed toward boys , with a sex ratio of 4 : 1 ( Fombonne , 2005 ) . Although many monogenic and chromosomal causes of ID are known , a " multiple hit " / oligogenic model is emerging , where combinations of variants are necessary to disrupt normal neuronal development and underlie a range of disorders from idiopathic epilepsy to autism and ID ( Coe et al , 2012 ) . Many genes involved in synaptic function were shown to play a role in neurodevelopmental disorders ( Gilman et al , 2011 ) . "
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    EMBO Molecular Medicine 04/2014; 6(12). DOI:10.1002/emmm.201303235 · 8.67 Impact Factor
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    • "Both The International Schizophrenia Consortium (2008) and Pinto et al. (2010) exploited this strategy, and report significant case-control burden differences. Further, a recent review of the role of CNVs in neurodevelopmental disorders (Coe et al., 2012) concluded that a greater burden of larger and/or more numerous small CNVs typically corresponds to greater phenotypic severity. Contemporary neurobiological theory of general intelligence recognizes the key role of a distributed network of frontal and parietal brain structures (Gläscher et al., 2010; Jung & Haier, 2007), and much evidence supports the hypothesis that the brains of more-intelligent individuals function more efficiently, in terms of energy consumption during a cognitively demanding task (Neubauer & Fink, 2009). "
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