Differences in Copy Number Variation between Discordant Monozygotic Twins as a Model for Exploring Chromosomal Mosaicism in Congenital Heart Defects

Abstract

Studies addressing the role of somatic copy number variation (CNV) in the genesis of congenital heart defects (CHDs) are scarce, as cardiac tissue is difficult to obtain, especially in non-affected individuals. We explored the occurrence of copy number differences in monozygotic (MZ) twins discordant for the presence of a CHD, as an illustrative model for chromosomal mosaicism in CHDs. Array comparative genomic hybridization was performed on peripheral blood-derived DNA obtained from 6 discordant MZ twin pairs and on sex-matched reference samples. To identify CNV differences between both twin members as well as potential CNVs in both twins contributing to the phenotype, DNA from each twin was hybridized against its co-twin, and against a normal control. Three copy number differences in 1 out of 6 MZ twin pairs were detected, confirming the occurrence of somatic CNV events in MZ twins. Further investigation by copy number and (epi)genome sequencing analyses in MZ twins, discordant for the presence of CHDs, is required to improve our knowledge on how postzygotic genetic, environmental and stochastic factors can affect human heart development.

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

“…Postnatal studies that reported the different distribution of CNVs in discordant MZ twins are involved in many types of diseases, including CHD, urorectal malformations, schizophrenia, Parkinson disease, congenital diaphragmatic hernia, esophageal atresia, attention problems and so on. The reported conclusions were contradictory.…”

“…revealed likely candidate genes and CNVs for the discordance of four of the six MZ twin pairs for Schizophrenia. Breckpot et al . recently identified disease‐causing de novo CNVs in one affected twin out of six MZ twin pairs discordant for congenital heart defects.…”

Monozygotic Twins with 17q21.31 Microdeletion Syndrome

“…Rio et al (2013) reported a phenotypically and genetically discordant monozygotic twin pair carrying a 2p25.3 deletion in one twin and mosaicism with one third of cells with the 2p25.3 deletion, one third with a 2p25.3 duplication, and one third of normal cells in the other one. Other recent studies of monozygotic twin pairs discordant for breast cancer (Lasa et al, 2010), schizophrenia (Ono et al, 2010) or congenital heart defect (Breckpot et al, 2012) also identified no CNV differences explaining the discordance.…”

Differences in the Expression of TLR-2, NOD2, and NF-κB in Placenta Between Twins

“…Phenotypic discordance between MZ twins can be also attributed to de novo events such as chromosomal mosaicism (e.g., the discordant karyotypes mos 47, XX; + 21/46, XX; and 46, XX) (Choi et al 2013), differing copy number variations (Breckpot et al 2012) and distinct single nucleotides (Castellani et al 2015). Postzygotic point mutations have been found to be the source of MZ twin discordance in oral-facial-digital syndrome type 1, neurofibromatosis type 1, Van der Woude syndrome, Joubert syndrome, and Darier’s disease (Czyz et al 2012).…”