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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Hall JG : Twinning. Lancet 2003; 362: 735–743.
Kaminsky ZA, Tang T, Wang SC et al: DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 2009; 41: 240–245.
Kimani JW, Shi M, Daack-Hirsch S et al: X-chromosome inactivation patterns in monozygotic twins and sib pairs discordant for nonsyndromic cleft lip and/or palate. Am J Med Genet 2007; 143A: 3267–3272.
Machin GA : Some causes of genotypic and phenotypic discordance in monozygotic twin pairs. Am J Med Genet 1996; 61: 216–228.
Streit A, Sommer RJ : Genetics: random expression goes binary. Nature 2010; 463: 891–892.
Bruder CE, Piotrowski A, Gijsbers AA et al: Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am J Human Genet 2008; 82: 763–771.
Baranzini SE, Mudge J, van Velkinburgh JC et al: Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature 2010; 464: 1351–1356.
Holder AM, Klaassens M, Tibboel D, de Klein A, Lee B, Scott DA : Genetic factors in congenital diaphragmatic hernia. Am J Human Genet 2007; 80: 825–845.
Shaw-Smith C : Oesophageal atresia, tracheo-oesophageal fistula, and the VACTERL association: review of genetics and epidemiology. J Med Genet 2006; 43: 545–554.
Sunagawa S, Kikuchi A, Yoshida S et al: Dichorionic twin fetuses with VACTERL association. J Obstet Gynaecol Res 2007; 33: 570–573.
Depaepe A, Dolk H, Lechat MF : The epidemiology of tracheo-oesophageal fistula and oesophageal atresia in Europe. EUROCAT Working Group. Arch Dis Child 1993; 68: 743–748.
Farquhar J, Carachi R, Raine PA : Twins with oesophageal atresia and the CHARGE association. Eur J Pediatr Surg 2002; 12: 56–58.
Khan RA, Narashimhan KL : Discordance in twins for esophageal atresia with tracheoesophageal fistula. Indian J Pediatr 2009; 76: 334–335.
Ohno K, Nakamura T, Azuma T et al: Esophageal atresia with tracheoesophageal fistula in both members of monozygotic twins. Pediatr Surg Int 2008; 24: 1137–1139.
Orford J, Glasson M, Beasley S, Shi E, Myers N, Cass D : Oesophageal atresia in twins. Pediatr Surg Int 2000; 16: 541–545.
Trobs RB, Knupffer M, Schutz A, Cernaianu G, Hirsch W, Regenthal R : Congenital oesophageal atresia discordant for tracheo-oesophageal fistula occurring in a set of dizygotic twins. Eur J Pediatr Surg 2006; 16: 260–264.
Donahoe PK, Noonan KM, Lage K : Genetic tools and algorithms for gene discovery in major congenital anomalies. Birth Defects Res 2009; 85: 6–12.
Lau ST, Kim SS, Ledbetter DJ, Healey PJ : Fraternal twins with Morgagni hernias. J Pediatr Surg 2005; 40: 725–727.
Machado AP, Ramalho C, Portugal R et al: Concordance for bilateral congenital diaphragmatic hernia in a monozygotic dichorionic twin pair - first clinical report. Fetal Diagn Ther 2010; 27: 106–109.
Pober BR, Lin A, Russell M et al: Infants with Bochdalek diaphragmatic hernia: sibling precurrence and monozygotic twin discordance in a hospital-based malformation surveillance program. Am J Med Genet 2005; 138A: 81–88.
Conlin LK, Thiel BD, Bonnemann CG et al: Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis. Hum Mol Genet 2010; 19: 1263–1275.
Veenma D, Beurskens N, Douben H et al: Comparable low-level mosaicism in affected and non affected tissue of a complex CDH patient. PLoS One 2010; 5: e15348.
Shaffer LG, Kashork CD, Saleki R et al: Targeted genomic microarray analysis for identification of chromosome abnormalities in 1500 consecutive clinical cases. J Pediatr 2006; 149: 98–102.
Ballif BC, Rorem EA, Sundin K et al: Detection of low-level mosaicism by array CGH in routine diagnostic specimens. Am J Med Genet A 2006; 140: 2757–2767.
Xiang B, Li A, Valentin D, Nowak NJ, Zhao H, Li P : Analytical and clinical validity of whole-genome oligonucleotide array comparative genomic hybridization for pediatric patients with mental retardation and developmental delay. Am J Med Genet A 2008; 146A: 1942–1954.
Shaikh TH, Gai X, Perin JC et al: High-resolution mapping and analysis of copy number variations in the human genome: a data resource for clinical and research applications. Genome Res 2009; 19: 1682–1690.
Scott DA, Klaassens M, Holder AM et al: Genome-wide oligonucleotide-based array comparative genome hybridization analysis of non-isolated congenital diaphragmatic hernia. Hum Mol Genet 2007; 16: 424–430.
Excoffon KJ, Avenarius MR, Hansen MR et al: The Coxsackievirus and Adenovirus Receptor: a new adhesion protein in cochlear development. Hear Res 2006; 215: 1–9.
Raschperger E, Neve EP, Wernerson A, Hultenby K, Pettersson RF, Majumdar A : The coxsackie and adenovirus receptor (CAR) is required for renal epithelial differentiation within the zebrafish pronephros. Dev Biol 2008; 313: 455–464.
Razzaghian HR, Shahi MH, Forsberg LA et al: Somatic mosaicism for chromosome X and Y aneuploidies in monozygotic twins heterozygous for sickle cell disease mutation. Am J Med Genet 2010; 152A: 2595–2598.
Hasler R, Begun A, Freitag-Wolf S et al: Genetic control of global gene expression levels in the intestinal mucosa: a human twin study. Physiol Genomics 2009; 38: 73–79.
Notini AJ, Craig JM, White SJ : Copy number variation and mosaicism. Cytogenet Genome Res 2008; 123: 270–277.
Yurov YB, Iourov IY, Vorsanova SG et al: Aneuploidy and confined chromosomal mosaicism in the developing human brain. PloS One 2007; 2: e558.
Piotrowski A, Bruder CE, Andersson R et al: Somatic mosaicism for copy number variation in differentiated human tissues. Hum Mutat 2008; 29: 1118–1124.
De S. : Somatic mosaicism in healthy human tissues. Trends Genet 2011; 27: 217–223.
Mathew SJ, Hansen JM, Merrell AJ et al: Connective tissue fibroblasts and Tcf4 regulate myogenesis. Development 2011; 138: 371–384.
Hansson O, Zhou Y, Renström E et al: Molecular function of TCF7L2: Consequences of TCF7L2 splicing for molecular function and risk for type 2 diabetes. Curr Diab Rep 2010; 10 (6): 444–451.
Nakamura F, Heikkinen O, Pentikainen OT et al: Molecular basis of filamin A-FilGAP interaction and its impairment in congenital disorders associated with filamin A mutations. PLoS One 2009; 4: e4928.
Su ZJ, Hahn CN, Goodall GJ et al: A vascular cell-restricted RhoGAP, p73RhoGAP, is a key regulator of angiogenesis. Proc Natl Acad Sci USA 2004; 101: 12212–12217.
Girirajan S, Rosenfeld JA, Cooper GM et al: A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet 2010; 42: 203–209.
Acknowledgements
We would like to thank all patients, specifically all twins and their parents for making this study possible. Also, we thank Tom de Vries-Lentsch for his help in preparing the figures. This study was funded by the Sophia's Children's Hospital Foundation for Medical Research, Rotterdam, The Netherlands (SSWO 493 and 551). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Veenma, D., Brosens, E., de Jong, E. et al. Copy number detection in discordant monozygotic twins of Congenital Diaphragmatic Hernia (CDH) and Esophageal Atresia (EA) cohorts. Eur J Hum Genet 20, 298–304 (2012). https://doi.org/10.1038/ejhg.2011.194
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/ejhg.2011.194
Keywords
This article is cited by
-
Technical strategy for monozygotic twin discrimination by single-nucleotide variants
International Journal of Legal Medicine (2024)
-
The Impact of Variation in Twin Relatedness on Estimates of Heritability and Environmental Influences
Behavior Genetics (2018)
-
Twin pregnancy complicated by esophageal atresia, duodenal atresia, gastric perforation, and hypoplastic left heart structures in one twin: a case report and review of the literature
Journal of Medical Case Reports (2017)
-
Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias
Nature Genetics (2015)
-
Whole genome comparison of donor and cloned dogs
Scientific Reports (2013)
