Molecular Genetic Causes of Discordance in Monozygotic Twins

Abstract

Abstract 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.