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.
"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 . "
"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 ) . "
[Show abstract][Hide abstract] ABSTRACT: Intellectual disability (ID) and autism spectrum disorders (ASDs) are complex neuropsychiatric conditions, with overlapping clinical boundaries in many patients. We identified a novel intragenic deletion of maternal origin in two siblings with mild ID and epilepsy in the CADPS2 gene, encoding for a synaptic protein involved in neurotrophin release and interaction with dopamine receptor type 2 (D2DR). Mutation screening of 223 additional patients (187 with ASD and 36 with ID) identified a missense change of maternal origin disrupting CADPS2/D2DR interaction. CADPS2 allelic expression was tested in blood and different adult human brain regions, revealing that the gene was monoallelically expressed in blood and amygdala, and the expressed allele was the one of maternal origin. Cadps2 gene expression performed in mice at different developmental stages was biallelic in the postnatal and adult stages; however, a monoallelic (maternal) expression was detected in the embryonal stage, suggesting that CADPS2 is subjected to tissue- and temporal-specific regulation in human and mice. We suggest that CADPS2 variants may contribute to ID/ASD development, possibly through a parent-of-origin effect.
EMBO Molecular Medicine 04/2014; 6(12). DOI:10.1002/emmm.201303235 · 8.67 Impact Factor
"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). "
[Show abstract][Hide abstract] ABSTRACT: Although twin, family, and adoption studies have shown that general cognitive ability (GCA) is substantially heritable, GWAS has not uncovered a genetic polymorphism replicably associated with this phenotype. However, most polymorphisms used in GWAS are common SNPs. The present study explores use of a different class of genetic variant, the copy-number variant (CNV), to predict GCA in a sample of 6199 participants, combined from two longitudinal family studies. We aggregated low-frequency (< 5%) CNV calls into eight different mutational burden scores, each reflecting a different operationalization of mutational burden. We further conducted three genome-wide association scans, each of which utilized a different subset of identified low-frequency CNVs. Association signals from the burden analyses were generally small in effect size, and none were statistically significant after a careful Type I error correction was applied. No signal from the genome-wide scans significantly differed from zero at the adjusted Type I error rate. Thus, the present study provides no evidence that CNVs underlie heritable variance in GCA, though we cannot rule out the possibility of very rare or small-effect CNVs for this trait, which would require even larger samples to detect. We interpret these null results in light of recent breakthroughs that aggregate SNP effects to explain much, but not all, of the heritable variance in some quantitative traits.
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