CNV Analysis in Monozygotic Twin Pairs Discordant for Urorectal Malformations

Abstract

Early post-twinning mutational events can account for discordant phenotypes in monozygotic (MZ) twin pairs. Such mutational events may comprise genomic alterations of different sizes, ranging from single nucleotides to large copy-number variations (CNVs). Anorectal malformations (ARM) and the bladder exstrophy-epispadias complex (BEEC) represent the most severe end of the urorectal malformation spectrum. Recently, CNV studies in patients with sporadic ARM and the BEEC have identified de novo events that occur in specific chromosomal regions. We hypothesized that early arising, post-twinning CNVs might contribute to discordance in MZ twin pairs with ARM or the BEEC; knowledge of such CNVs might help to identify additional chromosomal regions involved in the development of these malformations. We investigated four discordant MZ twin pairs (three ARM and one BEEC) using molecular karyotyping arrays comprising 1,140,419 markers with a median marker spacing of 1.5 kb. Filtering the coding regions for possible disease-causing post-twinning de novo CNVs present only in the affected twin, but not in the unaffected twin or the parents, identified a total of 136 CNVs. These 136 CNVs were then filtered against publicly available databases and finally re-evaluated visually. No potentially causative CNV remained after applying these filter criteria. Our results suggest that post-twinning CNV events that affect coding regions of the genome did not contribute to the discordant phenotypes in MZ twin pairs that we investigated. Possible causes for the discordant phenotypes include changes in regulatory elements or smaller genetic changes within coding regions which may be detectable by whole-exome sequencing.

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

“…The reported conclusions were contradictory. Baudisch et al . showed that no potentially causative CNV remained after applying the filter criteria for detection CNVs leading to urorectal malformations.…”

“…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.…”

“…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.…”

“…recently identified disease‐causing de novo CNVs in one affected twin out of six MZ twin pairs discordant for congenital heart defects. But the results of Baudisch et al . suggested post‐twinning CNV events did not contribute to the four cases with discordant urorectal malformations in MZ twin pairs they investigated.…”

Single Nucleotide Variants in A Family of Monozygotic Twins Discordant for the Phenotype Congenital Megaureter: A Genomic Analysis

“…Studies with monozygotic twins can be decisive in the elucidation of the molecular mechanisms involved in the development of congenital diseases in humans, especially because, in contrast to other individuals, monozygotic twins share similar prenatal environments as well as a common genetic background [13]. In this study, we identified 40,123 SNVs in the proband.…”