Whole Genome and Exome Sequencing of Monozygotic Twins with Trisomy 21, Discordant for a Congenital Heart Defect and Epilepsy

Abstract

Congenital heart defects (CHD) occur in 40% of patients with trisomy 21, while the other 60% have a structurally normal heart. This suggests that the increased dosage of genes on chromosome 21 is a risk factor for abnormal heart development. Interaction of genes on chromosome 21 or their gene products with certain alleles of genes on other chromosomes could contribute to CHD. Here, we identified a pair of monozygotic twins with trisomy 21 but discordant for a ventricular septal defect and epilepsy. Twin-zygosity was confirmed by microsatellite genotyping. We hypothesized that some genetic differences from post-twinning mutations caused the discordant phenotypes. Thus, next generation sequencing (NGS) technologies were applied to sequence both whole genome and exome of their leukocytes. The post-analyses of the sequencing data revealed 21 putative discordant exonic variants between the twins from either genome or exome data. However, of the 15 variants chosen for validation with conventional Sanger sequencing, these candidate variants showed no differences in both twins. The fact that no discordant DNA variants were found suggests that sequence differences of DNA from leukocytes of monozygotic twins might be extremely rare. It also emphasizes the limitation of the current NGS technology in identifying causative genes for discordant phenotypes in monozygotic twins.

Discordant clinical phenotype in monozygotic twins with Alagille syndrome: Possible influence of non‐genetic factors

“…In this mechanism, during the somatic cell division, additional genetic alterations are introduced as a second‐hit, which influences the phenotypic manifestation of the syndrome. However, it appears that not all phenotypic discordance is explained by somatic mosaicism as demonstrated by the failure of identifying a mutation explaining the phenotypic spectrum of monozygotic Down syndrome twins by whole genome and exome sequencing [Chaiyasap et al, ]. In our patient, somatic mosaicism for the disease causing mutation can be ruled out, but we cannot rule out a second, mosaic mutation in the genome that occurred in only one twin.…”

Whole‑genome sequencing of a monozygotic twin discordant for systemic lupus erythematosus

“…The invalidation of the selected discordant variants in the present study was consistent with previous similar studies. The studies by Baranzini et al (31), Chaiyasap et al (32) and Solomon et al (33) did not identify any discordant variants in monozygotic twins discordant for multiple sclerosis, congenital heart defect or vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies and limb abnormalities, respectively. By contrast, Reumers et al (30) and Tang et al (18) identified discordant variants in the monozygotic twins discordant for schizophrenia.…”

“…It is possible that the sequencing coverage of the present study had no sufficient power to identify de novo variants linked with SLE. ii) DNA in leukocytes may not be an ideal sample for studying monozygotic twins discordant for phenotypes (32,35). In pregnancy, most monozygotic twins are monochorionic.…”

Two cases of atypical twinning: Phenotypically discordant monozygotic and conjoined twins

“…However, in some discordant pairs, no nucleotide sequencing differences were found by next‐generation sequencing. Conversely, copy number and point mutations were identified in concordant adult MZ twins; however, the estimated mutation rate of 1.2 × 10 −7 per base pair per twin pair makes the biological significance of these nucleotide differences unclear . While these reports do not provide evidence specifically for fission or fusion, they underscore the complexity of the biological milieu surrounding the twinning event—or sequence of events—and subsequent development of the cotwins.…”