First prenatal detection of semi-identical twins

Published 15 March 2019

A case report of children conceived from one egg and two sperm cells who are neither identical nor fraternal twins - but fit 'somewhere in between'

The first prenatally identified pair of semi-identical (sesquizygotic) twins have been described in a case report from a team of maternal-fetal medicine specialists from the Australian Queensland University of Technology. Writing in the New England Journal of Medicine, they report that the boy and the girl, now age four, are identical with respect to their maternally inherited DNA, but share only 78% genetic resemblance from paternal contribution.(1) This remarkable ultra-rare postulated form of twinning thus finds its place somewhere between identical (monozygotic) and fraternal (dizygotic).

At a routine 6-week ultrasound examination, the presentation of a single placenta and chorion but two amniotic sacks misled the authors to consider the pregnancy in the 28-year-old Australian mother as monozygotic. However, it was the ultrasound scan at 14-weeks revealing gender discordance which removed the monozygotic possibility and set off an extraordinary chronicle of prenatal genetic diagnostics.

Amniocentesis was performed to sample amniotic fluid and perform genetic analysis on fetal DNA. But much to the surprise of the group, karyotyping did not show a typical euploid chromosome arrangement for a girl (46XX) or a boy (46XY), nor a result indicating aneuploidy. Instead, the twins appeared chimeric, meaning that some cells in their body were XX and others XY. Twin 1’s XX/XY chimerism ratio was 47:53 and Twin 2's was 90:10, predicting potential domination towards male and female development respectively.

To gain insight into how fertilisation might lead to the chimeric twins, a pairwise SNP analysis was performed to identify specific parentally inherited DNA regions in the chimeric DNA of each twin. More complex genetic analysis confirmed that the cells of both twins had the same maternal set of genetic determinants (haplotype) located on each of their chromosomes. But, two distinct paternal haplotypes were present in the two chimeric cell populations. These three haplotypes thus pointed the authors towards an interpretation of this miraculous twinning phenomenon as a product of 'dispermic fertilization', whereby two sperm cells penetrate a single oocyte. This event is considered incompatible with life!

However in this case, a possible failure of the cortical reaction machinery in place to prevent polyspermy led to the cytoplasmic co-presence of three pronuclei: two paternal and one maternal. From then on, the authors hypothesise the occurrence of serial ectopic events, based largely on earlier literature generated in animals. Collectively, the authors term this sequence of events ‘heterogoneic cell division’.

A detailed archive revisit of 968 pairs of twins and large population-based sibling studies confirmed that the pair of sesquizygotic twins is the first recorded prenatally and only the second ever reported. The first case was recognised after birth back in 2007.(2)

Despite the gender ambiguity and medical consultation, the parents continued their pregnancy. The semi-identical twins, the identity of which is not disclosed, were delivered by c-section because of suspected fetal compromise and were confirmed as a phenotypically male and female. Despite some health complications of the female twin early in life, both are reported to be developmentally normal.

1. Gabbett MT, Laporte J, Sekar R, et al. Molecular support for heterogonesis resulting in sesquizygotic twinning. N Engl J Med 2019; 380: 842-849.
2. Souter VL, Parisi MA, Nyholt DR, et al. A case of true hermaphroditism reveals an unusual mechanism of twinning. Hum Genet 2007; 121: 179-185.