Sesquizygotic Twins...Who Knew That Could Happen?

The New England Journal of Medicine recently released a paper on an extremely rare set of boy/girl sesquizygotic twins. Early in the pregnancy, it was noted on ultrasound that the twins shared a placenta, indicating they were likely identical twins. Sesquizygotic twins have been reported in the literature before, but this is reportedly the first case of it being detected during a pregnancy.

Twins who share a placenta and an amniotic sac are called mono/mono twins (or mono-chorionic/mono-amniotic, in full). When the twins share a placenta but are each surrounded by their own amniotic sac, they are called mono/di twins.

Seeing mono/mono and mono/di twins is not unusual, and in most situations when this happens the twins are fully identical and of the same sex. These pregnancies are high-risk because of some complications that can arise when two babies share a sac and/or chorion (placenta). When in the same amniotic sac, twins’ umbilical cords can entangle or one twin might continue to develop even though their heart did not develop, a condition called acardia in which a twin can temporarily survive (with what is otherwise an immediately-lethal condition). When twins share a placenta, they may have unequal sharing of blood supply, leading to twin-twin transfusion syndrome.

What was shocking and must have caught the attention of the medical staff was that this mono/di twin set were of opposite sex! I can only imagine all of the scenarios that went through the mind of those in the ultrasound room. My genetic counseling brain would have immediately led me to think of a difference in sexual development (DSD) in one twin, rather than linking it back to something unexpected that occurred all of the way back at the time of conception.

The authors of the NEJM paper conjecture that something called heterogonesis occurred. The three sets of chromosomes appear to have formed a tripolar spindle apparatus. Say that three times fast! It took me some time to wrap my brain around this and how it could happen. I have heard of polar body twinning before, but heterogonesis and tripolar spindle apparatus were never-before-heard terms to me before yesterday.

Both twins also show traces of both genomes, meaning they are both hemi-chimeric. The authors simplified this to simply “chimeric” in the paper, but full chimerism - tetragametic chimerism - would mean there were four gametes involved, and in this case, there were only three.

Here’s the run-down on various types of twinning. I threw in chimerism because this is essentially reverse-twinning and thereby relevant to discussing numbers of eggs and sperm and egg fusion events.

• Monozygotic twins - one egg, one sperm, fertilized egg splits (also called “identical” twins)

• Dizygotic twins - two eggs, each fertilized separately by its own sperm (also called “fraternal” twins and no more similar genetically than typical siblings born at different times)

• Chimeric person* - two eggs, two sperm, the two fertilized eggs fuse early to form one person

• Sesquizygotic twins - one egg, fertilized by two sperm

* Referring here to someone chimeric at birth as a result of tetragametic fertilization, not someone who acquires chimerism after stem cell transplantation or has hemi-chimerism due to trigametic sesquizygotic twinning.

What happens most of the time when two sperm fertilize one egg? A condition called triploidy.

If a second sperm is able to enter an egg before the egg recognizes the first sperm and puts up its biological defenses, the event is called dispermy (pronounced “die-spermy” and also called diandry).

When an egg is maturing, it starts out with double the chromosomes it needs. It must kick out half of the chromosomes, so that it has the right number (23) before fusing with a sperm. An egg kicks out its extra set of chromosomes via polar bodies. Thus, most eggs only have 23 chromosomes when fertilized.

Dispermy (or diandry) typically results in triploidy (three full sets of chromosomes). Triploidy is actually quite common (estimated around 2% of pregnancies) but the extra set of chromosomes is devastating to fetal development and typically results in loss of the pregnancy, usually in the first trimester.

They might both start out as one egg and two sperm, but triploidy and a sesquizygotic twin pregnancy are distinct. This case report has me thinking, what would it look like if a pair of sesquizygotic twins did ancestry testing?

It depends if the ancestry test would be able to analyze the sample each twin provides!

A complication with this case is that each twin is hemi-chimeric, meaning they both carry BOTH cell lines (the cell line with DNA from the egg and sperm #1 and the cell line with DNA from the egg and sperm #2). So it is unclear what cell line or lines a buccal sample would contain, and whether any result would come of it. A sample on one or both twins could fail to result, like what we see happens to some people who try to have testing after a stem cell transplant.

If an ancestry test investigation were successful, we would expect the shared DNA between the twins to be around 75%. Their shared centimorgan amount would likely fall between that seen in self/identical twin situations (around 3400 cM, per ISOGG wiki) and that for “regular” siblings (around 2550 cM per ISOGG wiki). Thus theoretically these twins would share somewhere in the middle: 2975 cM*.

(*I worked out these numbers using the DNA Detectives chart as well, and they are similar in approximation. The Shared cM Project doesn’t provide a number for self/identical, so I could not calculate an average from that data.)

The chromosome browser view would likely show more fully identical regions (FIRs) than any other combination of relatives besides identical twins. And with mom’s chromosomes being shared in their entirety, the entire length of all of the chromosomes would be half-identical (HIR), in the areas where there is no full matching.

What a shocking revelation this case report is to the world of genetics. There are certainly more cases of this that have likely happened, but they have gone undetected due to no ultrasonography available, no early ultrasonography performed, or the sex being the same for both babies.

Thank you to Michael T. Gabbett and team for putting in all the hard work it takes to get a paper published in NEJM!

Now, back to trying to figure out hetergonesis….

Interested in reading the full paper but don’t subscribe to or have access to the New England Journal of Medicine? You can sign up for an account on their site and download up to three free articles per month, like you can for many online newspapers.