Semi-identical Twins Identified in Pregnancy for First Time

Brisbane boy and girl share mother’s DNA but have different genes from the father, in only the second case to be identified in history

Illustration of human gametes
JESPER KLAUSEN / SCIENCE PHOTO L

Australian doctors have identified the second set ever known of semi-identical twins, they report this week in The New England Journal of Medicine. In this case, the twins had been revealed to be sesquizygotic, i.e., semi-identical, while still in the womb, a first in medical history. 

Sesquizygotic represents a third type of ‘twinning’ between identical and fraternal, explains the team, with Prof. Nicholas Fisk, a fetal medicine specialist and deputy vice-chancellor (Research) at the University of New South Wales, Dr Michael Gabbett, a clinical geneticist at the Queensland University of Technology, who had observed an anomaly in the pregnancy process, and others.

The twins, a boy and a girl, are now four years old and living in Brisbane.

Identical twins form when one egg is fertilized by one sperm, creating one embryo, which splits into two identical embryos early in gestation. Identical twins have to be the same sex.

Fraternal, or non-identical, twins form from two eggs, each fertilized by a different sperm cell. The gender of the twins depends on the sex chromosome, X or Y, in each of the sperm cells

Double fertilization
QUT

But semi-identical or sesquizygotic twins are formed when one egg is, irregularly, fertilized by two different sperm cells. Like in the case of the fraternal twins, the sex of the twins depend on the sex chromosome in each of the father’s sperm cells: X or Y.

The Brisbane twins have identical maternal DNA, i.e., all the DNA they got from the mother is identical. But as far as the father’s DNA is concerned, they are like siblings. “Some of the cells contain the chromosomes from the first sperm while the remaining cells contain chromosomes from the second sperm, resulting in the twins sharing only a proportion rather 100 percent of the same paternal DNA,” says Gabbett.

This was the first case worldwide to identify semi-identical twins by genetic testing while they were still in the womb, says the team. The only other known case was identified in 2007, somewhere in the United States, after the children were born.

Suddenly, strange

Fisk, who led the fetal medicine team that cared for the mother and twins while based at Royal Brisbane and Women’s Hospital in 2014, explains how they realized something was – unusual.

Clinical geneticist and QUT Diagnostic Genomics course coordinator Dr. Michael Gabbett.
QUT

“The mother’s ultrasound at six weeks showed a single placenta and positioning of amniotic sacs that indicated she was expecting identical twins,” he said. But the ultrasound at 14 weeks showed the twins were male and female, which is impossible for identical twins.

Hmm. Seemingly identical twins with a single placenta, but different sex. Fearful of chromosome abnormality, the doctors carried out amniocentesis testing, checking both the amniotic fluid and the maternal blood. The amnio results indicated that the twins were non-identical, Fisk told Haaretz.

Finer testing was clearly the order of the day. So they carried out a massive DNA fingerprinting comparison with the parents. They checked about 500,000 SNPs or single nucleotide polymorphisms on every chromosome, Fisk says.

And that showed that the twins had identical DNA sequences inherited from the mother, like identical twins, but shared some but not all of the DNA inherited from their father, like non-identical twins or siblings.

Three’s too much company

Fetal medicine specialist and UNSW Deputy Vice-Chancellor (Research) Professor Nicholas Fisk
UNSW

Normal embryos have two sets of chromosomes – the basic genetic material: one from mother, one from father.

When a sperm penetrates the oocyte, the egg membrane changes in a process called the cortical reaction, locking out any other sperm. And if somehow two sperm cells wriggle through, it just doesn’t work.

If one egg is fertilized by two sperm, the zygote has three sets of chromosomes, one from the mother and two from the father. Double fertilization normally leads to embryo death, and fast.

“Most triploidy demise in early pregnancy, some occasionally persist into mid trimester and even towards birth but almost never afterwards,” Fisk says (in animals; sometimes this does happen in some plant species).

That said, Fisk tells Haaretz - some recent work in cattle embryos created by IVF showed that two sperms can fertilize a single oocyte to segregate into two normal cell lines, a process called heterogonesis.

“That’s what we believe happened here, with the two cell lines then aggregating into two separate twins,” he sums up.

So in the case of the Brisbane sesquizygotic twins, the oocyte was simultaneously fertilized by two of the father’s sperm cells, Fisk postulates. The fertilized zygote then seems to have divided up the three sets of chromosomes among groups of cells and then split, creating the twins. It can be said definitely that one of the father’s sperm cells had an X chromosome and the other a Y.

The only other known case of sesquizygotic twin boys was discovered in the U.S. and reported in the Journal of Human Genetics in 2007. Their identity has never been revealed. The giveaway was that one twin was male and the other was a hermaphrodite, with both male and female reproductive tissue - ovarian and testicular. Genetic investigation revealed that they had identical maternal DNA, but only shared about half the father’s genome.

A study of genetic data from 968 fraternal twins and their parents around the world found no other case of semi-identical twinning, Fisk says, adding sage advice: “We know this is an exceptional case of semi-identical twins. While doctors may keep this in mind in apparently identical twins, its rarity means there is no case for routine genetic testing.”