title: 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.
authors.affiliation: Interdepartment of Biomedical Sciences, Faculty of Graduate School, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Pongsathorn
authors.initials: P
authors.lastname: Chaiyasap
authors.affiliation: Interdepartment of Biomedical Sciences, Faculty of Graduate School, Chulalongkorn University, Bangkok, Thailand; Genome Institute, National Center for Genetic Engineering and Biotechnology, Khlong Nueng, Khlong Luang, Pathum Thani, Thailand.
authors.forename: Supasak
authors.initials: S
authors.lastname: Kulawonganunchai
authors.affiliation: Center of Excellence for Medical Genetics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, Thai Red Cross, Bangkok, Thailand.
authors.forename: Chalurmpon
authors.initials: C
authors.lastname: Srichomthong
authors.affiliation: Genome Institute, National Center for Genetic Engineering and Biotechnology, Khlong Nueng, Khlong Luang, Pathum Thani, Thailand.
authors.forename: Sissades
authors.initials: S
authors.lastname: Tongsima
authors.affiliation: Center of Excellence for Medical Genetics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, Thai Red Cross, Bangkok, Thailand.
authors.forename: Kanya
authors.initials: K
authors.lastname: Suphapeetiporn
authors.affiliation: Center of Excellence for Medical Genetics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, Thai Red Cross, Bangkok, Thailand.
authors.forename: Vorasuk
authors.initials: V
authors.lastname: Shotelersuk
mesh_terms: D001483:Base Sequence; D004314:Down Syndrome / Q000150:complications* / Q000235:genetics*; D004827:Epilepsy / Q000150:complications*; D059472:Exome / Q000235:genetics*; D023281:Genomics; D006345:Heart Septal Defects, Ventricular / Q000150:complications*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D054643:INDEL Mutation; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA