Molecular Genetic Causes of Discordance in Monozygotic Twins


Although monozygotic (MZ) twins arise from the same gametes and a single zygote, they can at times reveal molecular genetic discordance. Differences in ploidy, chromosomal rearrangements and structural anomalies as well as different copy number variations (CNVs), point mutation discordance and genetic mosaicism have all been documented in MZ siblings. Depending on the type and magnitude, genetic discordance may lead to markedly different phenotypes. Traditionally, the best‐evidenced type of discordance encompasses a range of chromosomal abnormalities, partly due to their significant multiple effects on a phenotype. In contrast, surveying for single nucleotide polymorphism and CNV discordance globally poses more challenges. In the recent decades, growing evidence for low‐level CNV and point mutation discordance as well as mosaicism has amassed, although their frequency and phenotypic significance are yet to be established. High‐throughput sequencing strategies are likely to provide answers.

Key Concepts:

  • Despite stemming from the same zygote, monozygotic twins may develop genetic discordance.

  • Postzygotic genetic alterations often result in genetic mosaicism in one or both of the twins.

  • Confirmed genetic discordance in MZ twins encompasses mainly known disorders with clear or multiple/global effects, including five extremely rare cases of point mutations responsible for monogenic disorders and a range of chromosomal abnormalities as well as a few cases of trinucleotide repeat disorder discordance.

  • The most common type of genetic discordance in MZ twins are aneuploidies, particularly 45,X0 monosomy and, to a lesser degree, trisomies 21, 15 and 13, whereas discordance for structural rearrangements is even less frequent.

  • In MZ twins affected by aneuploidies, somatic mosaicism often plays a critical role in phenotypic discordance.

  • Genome‐wide studies of SNP and CNV discordance in twins face technical difficulties and have not yet brought a definite answer, although there is limited evidence for very low‐level discordance.

  • It will be challenging to fully ascertain the magnitude of genetic discordance in twins due to possible small‐scale SNP and CNV mosaicism across different tissues.

Keywords: aneuploidy; CNV ; de novo mutations; discordance; genetic; twins


Baranzini SE , Mudge J , van Velkinburgh JC et al. (2010) Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature 464(7293): 1351–1356.

Bateman CM , Colman SM , Chaplin T et al. (2010) Acquisition of genome‐wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia. Blood 115(17): 3553–3558.

Biousse V , Brown MD , Newman NJ et al. (1997) De novo 14484 mitochondrial DNA mutation in monozygotic twins discordant for Leber's hereditary optic neuropathy. Neurology 49(4): 1136–1138.

Blakely EL , He L , Taylor RW et al. (2004) Mitochondrial DNA deletion in ‘identical’ twin brothers. Journal of Medical Genetics 41(2): e19.

Bonilla E , Younger DS , Chang HW et al. (1990) Partial dystrophin deficiency in monozygous twin carriers of the Duchenne gene discordant for clinical myopathy. Neurology 40(8): 1267–1270.

Bourthoumieu S , Yardin C , Terro F et al. (2005) Monozygotic twins concordant for blood karyotype, but phenotypically discordant: a case of ‘mosaic chimerism’. American Journal of Medical Genetics Part A 135(2): 190–194.

Breckpot J , Thienpont B , Gewillig M et al. (2012) Differences in copy number variation between discordant monozygotic twins as a model for exploring chromosomal mosaicism in congenital heart defects. Molecular Syndromology 2(2): 81–87.

Bruder CE , Piotrowski A , Gijsbers AA et al. (2008) Phenotypically concordant and discordant monozygotic twins display different DNA copy‐number‐variation profiles. American Journal of Human Genetics 82(3): 763–771.

Cheng PJ , Shaw SW , Shih JC and Soong YK (2006) Monozygotic twins discordant for monosomy 21 detected by first‐trimester nuchal translucency screening. Obstetrics and Gynecology 107(2 Pt 2): 538–541.

Dahoun S , Gagos S , Gagnebin M et al. (2008) Monozygotic twins discordant for trisomy 21 and maternal 21q inheritance: a complex series of events. American Journal of Medical Genetics Part A 146A(16): 2086–2093.

Demunain AL , Cobo AM , Huguet E et al. (1994) Ctg trinucleotide repeat variability in identical‐twins with myotonic‐dystrophy. Annals of Neurology 35(3): 374–375.

Devys D , Biancalana V , Rousseau F et al. (1992) Analysis of full fragile X mutations in fetal tissues and monozygotic twins indicate that abnormal methylation and somatic heterogeneity are established early in development. American Journal of Medical Genetics 43(1–2): 208–216.

Dixit A , Tanteles G , Ocraft K , McEwan A and Sarkar A (2012) Monozygotic twins discordant for trisomy 13: counselling and management issues. Journal of Perinatology 32(8): 639–641.

Ehli EA , Abdellaoui A , Hu YS et al. (2012) De novo and inherited CNVs in MZ twin pairs selected for discordance and concordance on attention problems. European Journal of Human Genetics 20(10): 1037–1043.

Fanconi G (1962) Weitere Fälle von wahrscheinlich eineiigen Zwillingen, von denen der eine gesund ist, der andere einen Mongolismus zeight. Helvetica Paediatrica Acta 17: 490.

Furukawa H , Oka S , Matsui T et al. (2013) Genome, epigenome and transcriptome analyses of a pair of monozygotic twins discordant for systemic lupus erythematosus. Human Immunology 74(2): 170–175.

Grayson BL , Smith ME , Thomas JW et al. (2010) Genome‐wide analysis of copy number variation in type 1 diabetes. PLoS One 5(11): 1–8.

Hata A , Suzuki Y , Kuroki Y and Matsui I (1982) Ring 18 mosaicism in identical twins. Human Genetics 62(4): 364–367.

Helderman‐van den Enden AT , Maaswinkel‐Mooij PD , Hoogendoorn E et al. (1999) Monozygotic twin brothers with the fragile X syndrome: different CGG repeats and different mental capacities. Journal of Medical Genetics 36(3): 253–257.

Heydanus R , Santema JG , Stewart PA , Mulder PG and Wladimiroff JW (1993) Preterm delivery rate and fetal outcome in structurally affected twin pregnancies: a retrospective matched control study. Prenatal Diagnosis 13(3): 155–162.

Juberg RC , Stallard R , Straughan WJ , Avotri KJ and Washington JW (1981) Clinicopathologic conference: a newborn monozygotic twin with abnormal facial appearance and respiratory failure. American Journal of Medical Genetics 10: 193–200.

Kaplan L , Foster R , Shen Y et al. (2010) Monozygotic twins discordant for neurofibromatosis 1. American Journal of Medical Genetics Part A 152A(3): 601–606.

Kondo S , Schutte BC , Richardson RJ et al. (2002) Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nature Genetics 32(2): 285–289.

Kruyer H , Mila M , Glover G et al. (1994) Fragile X syndrome and the (CGG)n mutation: two families with discordant MZ twins. American Journal of Human Genetics 54(3): 437–442.

Lacassie Y , Cortes F , Molina V and Montgomery AH (1993) Discordant phenotype due to ring 13‐chromosomal mosaic syndrome in one identical twin. American Journal of Human Genetics 53(3): 571.

Lasa A , Cajal TRY , Llort G et al. (2010) Copy number variations are not modifiers of phenotypic expression in a pair of identical twins carrying a BRCA1 mutation. Breast Cancer Research and Treatment 123(3): 901–905.

Lejeune J , Lafourcade J , Scharer K et al. (1962) Heterokaryotic monozygotism, normal twin and 21 trisomal twin. Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences 254: 4404–4406.

Lewi L , Blickstein I , Van Schoubroeck D et al. (2006) Diagnosis and management of heterokaryotypic monochorionic twins. American Journal of Medical Genetics Part A 140A(3): 272–275.

Machin GA (1996) Some causes of genotypic and phenotypic discordance in monozygotic twin pairs. American Journal of Medical Genetics 61(3): 216–228.

Maiti S , Kumar KHBG , Castellani CA , O'Reilly R and Singh SM (2011) Ontogenetic de novo copy number variations (CNVs) as a source of genetic individuality: studies on two families with MZD twins for schizophrenia. PLoS One 6(3): e17125.

Marcus‐Soekarman D , Hamers G , Velzeboer S et al. (2004) Mosaic trisomy 11p in monozygotic twins with discordant clinical phenotypes. American Journal of Medical Genetics Part A 124A(3): 288–291.

Montgomery GW , Campbell MJ , Dickson P et al. (2005) Estimation of the rate of SNP genotyping errors from DNA extracted from different tissues. Twin Research and Human Genetics 8(4): 346–352.

Nielsen J (1967) Inheritance in monozygotic twins. Lancet 2(7518): 717.

Norremolle A , Hasholt L , Petersen CB et al. (2004) Mosaicism of the CAG repeat sequence in the Huntington disease gene in a pair of monozygotic twins. American Journal of Medical Genetics Part A 130A(2): 154–159.

O'Donnell CPF , Pertile MD , Sheffield LJ and Sampson A (2004) Monozygotic twins with discordant karyotypes: a case report. Journal of Pediatrics 145(3): 406–408.

Ono S , Imamura A , Tasaki S et al. (2010) Failure to confirm CNVs as of aetiological significance in twin pairs discordant for schizophrenia. Twin Research and Human Genetics 13(5): 455–460.

Panas M , Karadima G , Markianos M , Kalfakis N and Vassilopoulos D (2008) Phenotypic discordance in a pair of monozygotic twins with Huntington's disease. Clinical Genetics 74(3): 291–292.

Pauli S , Schmidt T , Funke R et al. (2012) Discordant phenotype in monozygotic twins with mosaic trisomy 12p in lymphocytes. European Journal of Medical Genetics 55(8–9): 480–484.

Peláez Castro E , Saladrigas Socarrás C , Ruiz-Pérez A and Pérez Avila J (1991) Use of an indirect immunofluorescence probe for early detection of latent malaria. Revista Cubana de Medicina Tropical 43(3): 178–181.

Perlman EJ , Stetten G , Tuckmuller CM et al. (1990) Sexual discordance in monozygotic twins. American Journal of Medical Genetics 37(4): 551–557.

Ramsey KW , Slavin TP , Graham G et al. (2012) Monozygotic twins discordant for trisomy 13. Journal of Perinatology 32(4): 306–308.

Redondo L , Polo MA , Rodriguez F et al. (1999) Myotonic dystrophy: DNA instability in monozygotic twins. Revista De Neurologia 28(7): 711–713.

Rehder H , Schoner K , Kluge B et al. (2012) Klinefelter twins presenting with discordant aneuploidies, acardia, forked umbilical cord and with different gonadal sex despite monozygosity. Prenatal Diagnosis 32(2): 173–179.

Reumers J , De Rijk P , Zhao H et al. (2012) Optimized filtering reduces the error rate in detecting genomic variants by short‐read sequencing. Nature Biotechnology 30(1): 61–68.

Reuss A , Gerlach H , Bedow W et al. (2011) Monozygotic twins discordant for trisomy 18. Ultrasound in Obstetrics and Gynecology 38(6): 727–728.

Rio M , Royer G , Gobin S et al. (2012) Monozygotic twins discordant for submicroscopic chromosomal anomalies in 2p25.3 region detected by array CGH. Clinical Genetics 84: 31–36.

Robertson SP , Thompson S , Morgan T et al. (2006) Postzygotic mutation and germline mosaicism in the otopalatodigital syndrome spectrum disorders. European Journal of Human Genetics 14(5): 549–554.

Russell A , Moschos A , Butler LJ and Abraham JM (1966) Gonadal dysgenesis and its unilateral variant with testis in monozygous twins: related to discordance in sex chromosomal status. Journal of Clinical Endocrinology and Metabolism 26(12): 1282–1292.

Sasaki H , Emi M , Iijima H et al. (2011) Copy number loss of (src homology 2 domain containing)‐transforming protein 2 (SHC2) gene: discordant loss in monozygotic twins and frequent loss in patients with multiple system atrophy. Molecular Brain 4(24).

Sepulveda W , Wong AE and Ocaranza M (2010) Heterokaryotypic pregnancy: monozygotic monochorionic twins discordant for trisomy 13. Fetal Diagnosis and Therapy 28(2): 109–113.

Stemkens D , Broekmans FJ , Kastrop PM et al. (2007) Variant Klinefelter syndrome 47,X,i(X)(q10),Y and normal 46,XY karyotype in monozygotic adult twins. American Journal of Medical Genetics Part A 143A(16): 1906–1911.

Sugawara H , Iwamoto K , Bundo M et al. (2012) Hypermethylation of serotonin transporter gene in bipolar disorder detected by epigenome analysis of discordant monozygotic twins. Bipolar Disorders 14: 127–128.

Taylor DM , Thum MY and Abdalla H (2008) Dichorionic triamniotic triplet pregnancy with monozygotic twins discordant for trisomy 13 after preimplantation genetic screening: case report. Fertility and Sterility 90(5): 2017 e5–2017 e9.

Tsukamoto H , Inui K , Taniike M et al. (1993) Different clinical features in monozygotic twins: a case of 7q syndrome. Clinical Genetics 43(3): 139–142.

Vadlamudi L , Dibbens LM , Lawrence KM et al. (2010) Timing of de novo mutagenesis – a twin study of sodium‐channel mutations. New England Journal of Medicine 363(14): 1335–1340.

Veenma D , Brosens E , de‐Jong E et al. (2012) Copy number detection in discordant monozygotic twins of congenital diaphragmatic hernia (CDH) and esophageal atresia (EA) cohorts. European Journal of Human Genetics 20(3): 298–304.

Vogt J , Kohlhase J , Morlot S et al. (2011) Monozygotic twins discordant for neurofibromatosis type 1 due to a postzygotic NF1 gene mutation. Human Mutation 32(6): E2134–E2147.

Watson WJ , Katz VL , Albright SG , Rao KW and Aylsworth AS (1990) Monozygotic twins discordant for partial trisomy 1. Obstetrics and Gynecology 76(5 Pt 2): 949–951.

West PMH , Love DR , Stapleton PM and Winship IM (2003) Paternal uniparental disomy in monozygotic twins discordant for hemihypertrophy. Journal of Medical Genetics 40(3): 223–226.

Youssoufian H and Pyeritz RE (2002) Mechanisms and consequences of somatic mosaicism in humans. Nature Reviews Genetics 3(10): 748–758.

Zech NH , Wisser J , Natalucci G et al. (2008) Monochorionic‐diamniotic twins discordant in gender from a naturally conceived pregnancy through postzygotic sex chromosome loss in a 47,XXY zygote. Prenatal Diagnosis 28(8): 759–763.

Zwijnenburg PJG , Meijers‐Heijboer H and Boomsma DI (2010) Identical but not the same: the value of discordant monozygotic twins in genetic research. American Journal of Medical Genetics Part B‐Neuropsychiatric Genetics 153B(6): 1134–1149.

Further Reading

Al‐Awadi SA , Cuschieri A , Farag TI et al. (1983) Ullrich–Turner syndrome in monozygotic twins. American Journal of Medical Genetics 15(4): 537–542.

Beckmann JS , Estivill X and Antonarakis SE (2007) Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability. (In English). Nature Reviews Genetics 8(8): 639–646.

Costa T , Lambert M , Teshima I et al. (1998) Monozygotic twins with 45,X/46,XY mosaicism discordant for phenotypic sex. American Journal of Medical Genetics 75(1): 40–44.

Craddock N , Hurles ME , Cardin N et al. (2010) Genome‐wide association study of Cnvs in 16,000 Cases of eight common diseases and 3,000 shared controls. (In English). Nature 464(7289): 713.

Dallapiccola B , Stomeo C , Ferranti G , Di Lecce A and Purpura M (1985) Discordant sex in one of three monozygotic triplets. Journal of Medical Genetics 22(1): 6–11.

van Dongen J , Slagboom PE , Draisma HH , Martin NG and Boomsma DI (2012) ‘The continuing value of twin studies in the omics era’. Nature Reviews Genetics 13(9): 640–653.

Feuk L , Carson AR and Scherer SW (2006) Structural variation in the human genome. (In eng). Nature Reviews Genetics 7(2): 85–97.

Kato T , Iwamoto K , Kakiuchi C , Kuratomi G and Okazaki Y (2005) Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders. Molecular Psychiatry 10(7): 622–630.

Pescia G , Ferrier PE , Wyss‐Hutin D and Klein D (1975) 45,X Turners syndrome in monozygotic twin sisters. Journal of Medical Genetics 12(4): 390–396.

Shine IB and Corney G (1966) Turner's syndrome in monozygotic twins. Journal of Medical Genetics 3(2): 124–128.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Czyz, Witold, and Ramagopalan, Sreeram V(Sep 2013) Molecular Genetic Causes of Discordance in Monozygotic Twins. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025033]