Short summary

Monozygotic (MZ) twins are expected to be genetically identical. However, case reports on MZ twins with discordant phenotypes or genotypes are not rare. We look at MZ twin pairs in which at least one twin has a chromosomal aberration, and aim to describe the degree of phenotypic and genetic variation in members of such pairs. We hope to gain insight into the genetic mechanisms that lies behind clinical variation in MZ twins with chromosomal aberrations.

Rationale

Developed from a single ovum, monozygotic (MZ) twins are expected to be almost identical. Twin research design has traditionally assumed that MZ-twins are genetically identical. This assumption has been used for decades to estimate the importance of genetic and environmental influences on diseases and complex trait variations. It has been assumed that less than 100% concordance of disease among MZ twins support non-genetic (i.e. stochastic) factors involvement in pathogenesis.

However, a considerable number of MZ twins are not identical; e.g. one twin may have a genetic condition like Down syndrome while the other does not, or one twin may be more severely affected by a chromosomal aberration than the other.

What are the underlying causes of these unexpected differences in clinical expression or genotype in some MZ twin pairs?

The mechanisms that cause MZ twinning are still unknown. Dizygotic (DZ) twins are derived from the fertilization of two ova by two sperm, whereas MZ twins arise from fertilization of one ovum by one sperm, where after the fertilized ovum divides into two cell masses. Why and how the division of the ovum occurs is not fully understood. It is known, that the incidence of spontaneously conceived twins varies worldwide. However, the incidence of spontaneously conceived MZ twins is remarkably constant and independent of geographical and ethnic factors. Variation in twinning rates is therefore ascribed to variation in DZ twinning alone. So what causes MZ twinning?

These unanswered questions have inspired researchers to contrive new hypotheses regarding the mechanisms behind MZ twinning. J.G. Hall has put forward the hypothesis that MZ twinning arises due to discordance in the expression of genetic information in the cells of the fertilized ovum, e.g. due to a chromosomal aberration. As a consequence, MZ twins should be discordant for minor or major genetic aberrations, either completely or in a mosaic state.

Aim

The aim of this study was to describe the degree of variation in phenotype and genotype between the two members of MZ twin pairs using a structured clinical examination and a range of genetic analyzes.

In pairs in which only one twin is known with a chromosomal aberration, we will examine DNA from a blood sample as well as a skin biopsy, in order to detect mosaicism and explore the hypothesis of Hall.

In pairs in which both twins have a chromosomal aberration, we will examine whether any observable difference in phenotypes between the two individuals could be explained by genetic and epigenetic differences, and also look for mosaicism.

Description of the cohort

All live born twin pairs born in Denmark in the period of April 2nd 1968 to December 31st 2009, in which one or both twins have a chromosomal aberration, and who are categorized (by questionnaires) as MZ twins in the Danish Twin Registry, were invited to participate. 

Data and biological material

Twins with chromosomal aberrations were identified by linking the Danish Twin Registry to The Danish Cytogenetic Central Register.

By means of a structured standard clinical examination with additional description of any dysmorphic features, the individual degree of clinical expression of a chromosomal aberration is evaluated.

A complete medical history, family history and pedigree are recorded.

Zygosity will subsequently be confirmed by DNA analyzes as well.

Genetic analysis will be carried out on DNA from blood and skin samples (optional).

Methods applied will be karyotyping, examination of copy number variation by chromosome micro array analysis, Whole Exome amplification and epigenetic analyzes, e.g. methylation studies. 

Collaborating researchers and departments

Department of Clinical Genetics, Odense University Hospital and The Research Unit of Human Genetics, Institute of Clinical Research, University of Southern Denmark

• Professor and consultant Jens Michael Hertz PhD, DMSc
• Consultant Christina Ringmann Fagerberg
• Head of Department and consultant Lilian Bomme Ousager

The Danish Twin Registry, Institute of Public Health, University of Southern Denmark

• Professor and Head of Unit Kaare Christensen, PhD, DMSc