Is Identifying Extra X and Y Chromosomes a Good Idea, or Does it Invite Stigma?

Sequencing our genomes is a 21rst century phenomenon. Discrimination based on genetics dates back to the start of the eugenics movement in the 1880s. Will an effort to determine the sex chromosome constitutions of nearly 600,000 men whose DNA is being analyzed in the Million Veteran Program provide helpful health information – or highlight another possible source of genetic judgment?

Researchers at the University of Colorado Anschutz Medical Campus and collaborators across the US report the largest and most diverse study of men with extra X or Y chromosomes in the US. Their findings appear in the March 29, 2024 JAMA Network Open. The Million Veteran Program is a national effort considering how genes, lifestyle, military experiences, and environmental exposures affect health and wellness among veterans. It launched in 2011.

The Biology of Sex Chromosomes

In this age of nuanced gender definitions and flexible personal pronouns, the biology of sex chromosomes – the X and the Y – remains unchanged. A person with a Y is a male; without a Y, a female. A biological female is XX, and a male, XY.

Any other combination is considered “atypical” (you can’t say “abnormal” anymore). (See Embracing Diversity, Equity, and Inclusion in Genetics Textbooks and Testing.)

Not all species share sex chromosome systems. Male fruit flies, for example, aren’t XY like men, but XO. Male birds and snakes are ZZ, females ZW. Most astonishing is the slipper limpet, a type of snail with oblong shells that stick to each other, stacking up and washing up onto shorelines. Position in the stack determines sex, with the original end male, transitioning to female as position proceeds.

For humans who have an atypical sex chromosome constitution, symptoms are absent or subtle, slow to appear, and shared with other conditions. In fact, an extra sex chromosome might not be detected unless a person has a chromosome test, which might be in response to a specific set of symptoms, or during chromosome analysis of a fetus. Routine prenatal blood tests assess the most common chromosomes that are extra or missing – 13, 18, 21, and the X and Y. So geneticists estimate that less than 15 percent of people who actually have an unusual sex chromosome constitution are identified. And most of them are of Western European ancestry.

A news release accompanying publication of the new paper reads, “the results could lead to better diagnoses of these underrecognized conditions and earlier treatment of associated diseases.”

But is that a pathologicalization of a relatively harmless chromosomal variation?

Do I smell stigma? Or misattribution of cause?

The new study includes people who are XXY or XYY – biological males. Below is how I describe them in my textbook, Human Genetics: Concepts and Applications.

47,XXY Syndrome

Looking back, the man’s only indication of 47,XXY syndrome was small testes. When his extra X chromosome was detected when he was 25, suddenly his personality quirks made sense. As a child and teen, he had been very shy, had trouble making friends, and angered easily. Psychologists, psychiatrists, and therapists diagnosed learning disabilities. One said that the man would never be able to attend college. Yet he earned two bachelor’s degrees and is a software engineer. (This individual related his story for my book.)

About 1 in 500 males has the extra X of 47,XXY syndrome (once called Klinefelter syndrome). Only some have related characteristics.

Severely affected men have underdeveloped testes and prostate glands and sparse pubic and facial hair. They have long arms and legs, large hands and feet, and may develop breast tissue. They may be slow to learn, but they are usually not intellectually disabled unless they have more than two X chromosomes, which is rare. It is the most common genetic or chromosomal cause of infertility in the male.

47,XYY Syndrome

Having an extra Y chromosome has carried a stigma because of a misjudgment dating back to the 1960s.

In 1965, Patricia Jacobs surveyed 197 inmates at Carstairs, a high-security prison in Scotland. Of twelve men with unusual chromosomes, seven had an extra Y. Jacobs discovered the same association with an extra Y among patients at mental institutions. Soon, magazine covers featured “congenital criminals,” blaming aggressive behavior on the extra Y, which became known as Jacobs syndrome back when we named medical conditions after their discoverers.

47,XYY became a legal defense for committing a violent crime, and was a plot on the television show Law and Order. But it has never successfully been used in a legal defense due to biological uncertainty.

In the early 1970s, hospitals in England, Canada, Denmark, and Boston began screening newborns for XYY. Social workers and psychologists visited identified boys to offer “anticipatory guidance” on how patents should handle their toddling future criminals. By 1974, an outcry from geneticists halted the programs. Might singling out these boys on the basis of a few statistical studies invite self-fulfilling prophecy?

One male in 1,000 has an extra Y. Today, we know that 96 percent of males with an extra Y are not destined to become criminals, but may be tall and have acne. Problems with speech and understanding language are subtle, such as an inability to understand humor. Attaining skills like dressing and socializing may be delayed.

The higher prevalence of 47,XYY among men in prisons and psychiatric facilities may stem more from psychology than biology. Large body size may lead teachers, employers, parents, and others to expect more of these individuals, and a few may deal with this stress aggressively.

Identifying XXY and XYY Among a Million Veterans

The new study reported in JAMA Network Open checked the chromosomes of 595,612 men in the Million Veteran Program. One in 370 men had an extra X or Y, but only 14.2% had been clinically diagnosed by age 60. The investigators identified an extra X in 862 men and an extra Y in 747 men, which are similar to known frequencies in the general population.

Although these men had more health issues compared to matched controls, clearly the two conditions, XXY and XYY, have such mild and common manifestations that they often fly under the radar.

So should we routinely screen for sex chromosome constitution? With what we know today about XXY and XYY, detection of an extra sex chromosome wouldn’t be as damning as the newborn screening of the 1960s. Still, I can’t help but wonder whether it might fuel discrimination, even subtly.

First author Shanlee Davis provides perspective:

“One in 400 males have an additional X or Y chromosome, however 86 percent of these individuals are not diagnosed. This study supports that men with X and Y variations successfully serve in the US military but experience many medical and psychiatric comorbidities that could potentially be prevented with appropriate diagnosis and care.”

These include type 2 diabetes and cardiovascular disorders, which of course are also common in the general population. So why the need for a chromosome check?

“There’s still a lot we don’t know about these men who have gone years without a proper diagnosis. Studying this aging population will allow us to learn the risks associated with extra X and Y chromosomes, even when we do not know about the genetic difference clinically. Early identification of these conditions, which is now often happening prenatally, gives us an opportunity to prevent some of the illnesses associated with Klinefelter and Jacobs syndromes,” Davis added in a news release, unfortunately using eponyms, which stopped being used for genetic conditions in the 1990s.

Why?

The researchers are expanding their study to include data from other global biobanks.

I’m reminded of the words of mathematician Ian Malcolm of Jurassic Park fame, in the wake of escaped cloned dinosaurs rampaging through a theme park:

“Your scientists were so preoccupied with whether or not they could, they didn’t stop to think if they should.”

Why do men need to know that each of their cells carries an extra X or Y chromosome?

Infertility will make itself known, in time.

Symptoms or screening tests will reveal diabetes or cardiovascular disease, which can presumably be treated just as they would in a person with 46 chromosomes.

Sometimes, genetic information is not needed, or even dangerous.