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


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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    ABSTRACT: By definition, monozygotic (MZ) twins carry an identical set of genetic information. The observation of early post-twinning mutational events was shown to cause phenotypic discordance among MZ twin pairs. These mutational events comprise genomic alterations at different scales, ranging from single nucleotide changes to larger copy-number variations (CNVs) of varying sizes, as well as epigenetic changes. Here, we performed whole-exome sequencing (WES) in nine discordant MZ twins to identify somatic mutational events in the affected twin that might exert a dominant negative effect. Five of these MZ twin pairs were discordant for congenital heart defects (CHD), two for endocrine disorders, one for omphalocele, and one for congenital diaphragmatic hernia (CDH). Analysis of WES data from all nine MZ twin pairs using the de novo probability tool DeNovoGear detected only one apparent de novo variation in TMPRSS13 in one of the CHD-affected twins. Analysis of WES data from all nine MZ twin pairs by using standard filter criteria without the de novo probability tool DeNovoGear revealed a total of 6,657 variations in which both the twin pairs differed. After filtering for variations only present in the affected twins and absent in in-house controls, 722 variations remained. Visual inspection for read quality decreased this number to 12, present only in the affected twin. However, Sanger sequencing of the overall 13 variations failed to confirm the variation in the affected twin. These results suggest that somatic mutational events in coding regions do not seem to play a major role in the phenotypic expression of MZ discordant twin pairs.
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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.
    Full-text · Article · Feb 2014 · PLoS ONE
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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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    ABSTRACT: We have evaluated copy number variants (CNVs) in six monozygotic twin pairs discordant for schizophrenia. The data from Affymetrix® Human SNP 6.0 arrays™ were analyzed using Affymetrix® Genotyping Console™, Partek® Genomics Suite™, PennCNV, and Golden Helix SVS™. This yielded both program-specific and overlapping results. Only CNVs called by Affymetrix Genotyping Console, Partek Genomics Suite, and PennCNV were used in further analysis. This analysis included an assessment of calls in each of the six twin pairs towards identification of unique CNVs in affected and unaffected co-twins. Real time polymerase chain reaction (PCR) experiments confirmed one CNV loss at 7q11.21 that was found in the affected patient but not in the unaffected twin. The results identified CNVs and genes that were previously implicated in mental abnormalities in four of the six twin pairs. It included PYY (twin pairs 1 and 5), EPHA3 (twin pair 3), KIAA1211L (twin pair 4), and GPR139 (twin pair 5). They represent likely candidate genes and CNVs for the discordance of four of the six monozygotic twin pairs for this heterogeneous neurodevelopmental disorder. An explanation for these differences is ontogenetic de novo events that differentiate in the monozygotic twins during development.
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