Article

De novo and inherited CNVs in MZ twin pairs selected for discordance and concordance on Attention Problems

1] Avera Institute for Human Genetics, Avera Behavioral Health Center, Sioux Falls, SD, USA [2] Department of Psychiatry, University of South Dakota, Sioux Falls, SD, USA.
European journal of human genetics: EJHG (Impact Factor: 4.35). 04/2012; 20(10):1037-43. DOI: 10.1038/ejhg.2012.49
Source: PubMed

ABSTRACT

Copy number variations (CNVs) have been reported to be causal suspects in a variety of psychopathologic traits. We investigate whether de novo and/or inherited CNVs contribute to the risk for Attention Problems (APs) in children. Based on longitudinal phenotyping, 50 concordant and discordant monozygotic (MZ) twin pairs were selected from a sample of ∼3200 MZ pairs. Two types of de novo CNVs were investigated: (1) CNVs shared by both MZ twins, but not inherited (pre-twinning de novo CNVs), which were detected by comparing copy number (CN) calls between parents and twins and (2) CNVs not shared by co-twins (post-twinning de novo CNVs), which were investigated by comparing the CN calls within MZ pairs. The association between the overall CNV burden and AP was also investigated for CNVs genome-wide, CNVs within genes and CNVs outside of genes. Two de novo CNVs were identified and validated using quantitative PCR: a pre-twinning de novo duplication in a concordant-unaffected twin pair and a post-twinning deletion in the higher scoring twin from a concordant-affected pair. For the overall CNV burden analyses, affected individuals had significantly larger CNVs that overlapped with genes than unaffected individuals (P=0.008). This study suggests that the presence of larger CNVs may increase the risk for AP, because they are more likely to affect genes, and confirms that MZ twins are not always genetically identical.

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    • "In accordance with these observations, Breckpot et al. (2012) identified three possibly disease-causing de novo CNVs in one affected twin out of six MZ twin pairs discordant for CHD, and Kondo et al. (2002) identified a nonsense mutation in IRF6 in the affected twin only in MZ discordant twins for Van der Woude syndrome. Moreover, a posttwinning ß1.3 Mb de novo deletion had been identified in a concordant-affected twin pair with attention problems (AP; Ehli et al., 2012) that might be of value to explain the higher AP score in the twin showing the deletion. "
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    • "All the miRNA-CNVs clustered based on the point and type of origin showed biased contributions of miRNA-CNVs from mother compared to father. Though, earlier studies have reported diverse CNV transmission and de novo event rates in probands with several neurodevelopmental phenotypes and monozygotic twin studies [51]–[54], however, no such inheritance rate on the miRNA-CNVs has been performed before. miRNA-CNV frequency bias was observed on the CNV transmissions from maternal genome only, showing major contributions from deletion CNVs than duplications. "
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    ABSTRACT: MicroRNAs are involved in post-transcriptional down-regulation of gene expression. Variations in miRNA genes can severely affect downstream-regulated genes and their pathways. However, population-specific burden of CNVs on miRNA genes and the complexities created towards the phenotype is not known. From a total of 44109 CNVs investigated from 1715 individuals across 12 populations using high-throughput arrays, 4007 miRNA-CNVs (∼9%) consisting 6542 (∼5%) miRNA genes with a total of 333 (∼5%) singleton miRNA genes were identified. We found miRNA-CNVs across the genomes of individuals showing multiple hits in many targets, co-regulated under the same pathway. This study proposes four mechanisms unraveling the many complexities in miRNA genes, targets and co-regulated miRNA genes towards establishment of phenotypic diversity.
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    • "Using monozygotic twins, three somatic CNV events were found to be associated with discordance for congenital heart defects (Breckpot et al., 2012). Similarly, two de novo CNVs — a pre-twinning duplication and a post-twinning deletion were found to be associated with attention problems (Ehli et al., 2012). Another study looking at Rett syndrome in discordant monozygotic twins found differences in deoxyribonucleic acid (DNA) methylation between twins detected in fibroblasts in the upstream region of genes involved in brain function to be associated with the disease (Miyake et al., 2013). "
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