Copy number detection in discordant monozygotic twins of Congenital Diaphragmatic Hernia (CDH) and Esophageal Atresia (EA) cohorts

Abstract

The occurrence of phenotypic differences between monozygotic (MZ) twins is commonly attributed to environmental factors, assuming that MZ twins have a complete identical genetic make-up. Yet, recently several lines of evidence showed that both genetic and epigenetic factors could have a role in phenotypic discordance after all. A high occurrence of copy number variation (CNV) differences was observed within MZ twin pairs discordant for Parkinson's disease, thereby stressing on the importance of post-zygotic mutations as disease-predisposing events. In this study, the prevalence of discrepant CNVs was analyzed in discordant MZ twins of the Esophageal Atresia (EA) and Congenital Diaphragmatic Hernia (CDH) cohort in the Netherlands. Blood-derived DNA from 11 pairs (7 EA and 4 CDH) was screened using high-resolution SNP arrays. Results showed an identical copy number profile in each twin pair. Mosaic chromosome gain or losses could not be detected either with a detection threshold of 20%. Some of the germ-line structural events demonstrated in five out of eleven twin pairs could function as a susceptible genetic background. For example, the 177-Kb loss of chromosome 10q26 in CDH pair-3 harbors the TCF7L2 gene (Tcf4 protein), which is implicated in the regulation of muscle fiber type development and maturation. In conclusion, discrepant CNVs are not a common cause of twin discordancy in these investigated congenital anomaly cohorts.

Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome

“…Thus, CNV differences between twins might be induced by environmental factors. However, there are also lines of evidence that suggest CNVs do not differ between MZ twins [15], [45], [46]. In our study, candidate CNV loci identified by a combination of next-generation sequencing and a CNV/SNP chip assay could not be validated by a digital droplet-based PCR quantitative assay.…”

MCDA twins with discordant malformations: submicroscopic chromosomal anomalies detected by chromosomal microarray analysis and clinical outcomes

“…The studies showed discrepant CNVs in discordant MZ twins focusing on mental disease or Parkinson disease. But postnatal studies that investigated cases with congenital malformations mostly showed discrepant CNVs are not a common cause of twin discordancy . These results demonstrated that the rather high prevalence of discrepant CNVs in discordant schizophrenia and Parkinson disease MZ twins may have been generated later in life and age‐accumulated CNVs events may play an important role in the development of these diseases.…”

“…In a word, we have no adequacy evidence to conclude that CNV gain at 2q13 of the four cases in our study is pathogenic. Postnatal studies that reported the different distribution of CNVs in discordant MZ twins are involved in many types of diseases, including CHD, 6 urorectal malformations, 7 schizophrenia, 5 Parkinson disease, 24 congenital diaphragmatic hernia, esophageal atresia, 25 attention problems 26 and so on. The reported conclusions were contradictory.…”

Whole genome comparison of donor and cloned dogs

“…S1), in order to compare them with the dog assembly. To investigate the level of genomic difference in the dogs, we compared it with the genomes of human monozygotic twins (ethnic Korean, female), which serve as an example of natural cloning and were assumed to be of identical genetic make-up6. We carried out a genome-wide analysis in terms of single nucleotide variation (SNV), copy number variation (CNV), structural variation (SV), and telomere lengths (Fig.…”