Molecular Support for Heterogonesis Resulting in Sesquizygotic Twinning

Today’s GEITP topic is an obstetric curiosity — sometimes found clinically during fertilization. Twins are traditionally classified as monozygotic (“identical”) or dizygotic (“fraternal”). Monozygotic twinning results in genetically identical (more or less identical, although many epigenetic differences between twin-pairs have been demonstrated) individuals (i.e. derived from a single sperm and egg). On the other hand, dizygotic twins share approximately 50% of their DNA sequence identity, the same as full siblings (i.e. two individual sperm fertilizing two separate oocytes). Sesquizygosity is a third form of twinship, in which individuals share between 50% and 100% of genetic identity-by-state (i.e. the number of shared alleles; each gene comprises two alleles, one from each parent). Twins resulting from the “involvement of two male pronuclei in the fertilization of two female meiotic products” (called sesquizygosity) thus result in an “exceptional intermediate” — somewhere between monozygotic and dizygotic twins.

Two thirds of monozygotic twin pregnancies have a monochorionic placenta (i.e. twins sharing the same placenta) — which is associated with increased abnormalities during the newborn period. Accordingly, chorionicity (i.e. assessment of the number of chorions in the placenta that supply blood and nourishment to the developing fetuses) is now routinely determined via ultrasonography early in the pregnancy. The long-held assumption that monochorionic twins are definitively monozygotic has been challenged by rare case reports of two types:

First, more than a dozen studies have documented heterokaryotypic twins (i.e. twins that differ with respect to inherent chromosomal anomalies) who typically exhibit mosaic sex-chromosome aneuploidy (e.g. XXY, XYY, XXXY in some cells — i.e. instead of the usual XX vs XY baby) that is attributed to postzygotic nondisjunction [three types of nondisjunction include: [a] failure of a pair of homologous chromosomes to separate during the 1st meiosis; [b] failure of sister chromatids to separate during the 2nd meiosis; and [c] failure of sister chromatids to separate during mitosis. Nondisjunction results in aneuploid (having abnormal chromosome numbers) daughter cells].

Second, there have been some reports of a smaller number of dizygotic monochorionic twin pregnancies — typically associated with

euploid chimerism (i.e. two distinct cell populations within the body, both having the normal complement of chromosomes), and with “assisted reproduction” (e.g. in vitro fertilization).

Authors [see attached article] report a monochorionic-twin pregnancy with fetal sex-chromosome discordance. Genotyping of amniotic fluid from each sac showed that the twins were maternally identical, but chimerically shared 78% of their paternal genome, which makes them genetically “in between monozygotic and dizygotic”, hence, the term “sesquizygotic.” Authors observed no evidence of sesquizygosis in 968 other dizygotic twin-pairs — whom they had screened by means of whole-genome single-nucleotide variant (SNV) genotyping. Data from published suppositories (or, more accurately, repositories) also show that sesquizygosis is a rare event. The authors’ detailed genotyping implicates chimerism has arisen at heterogonesis (i.e. the juncture of zygotic division) — as the likely initial step in the causation of sesquizygosis.


N Engl J Med 28 Feb 2019; 380: 842-849

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