Oldest Case of Klinefelter Syndrome Diagnosed in Ancient Skeleton

A multidisciplinary team of researchers have discovered what is believed to be the oldest case of Klinefelter syndrome in a 1,000-year-old skeleton. The finding is outlined in a new study published in The Lancet.

What is Klinefelter syndrome?  

DNA, the “blueprint” that encodes the proteins required for biological functions, is efficiently packaged into a cell’s nucleus, tightly wound around proteins known as histones. These threads of DNA are arranged into chromosomes, inherited from our parents – 23 from our mother and 23 from our father. The 23^rd pair of chromosomes are known as the “sex chromosomes” as they determine whether an individual is born male or female. Individuals assigned female at birth inherit two X chromosomes, whereas those assigned male at birth inherit one X and one Y chromosome.

Klinefelter syndrome is a genetic condition that occurs when a male is born with an extra copy of the X chromosome, affecting an estimated 1 in 1,000 individuals. Symptoms of Klinefelter syndrome may include delays in growth and development and/ or issues with fertility and low sex drive. Diagnosis is often achieved using hormonal testing and chromosome (or karyotype) analysis to investigate the shape and number of chromosomes.

The oldest known case of Klinefelter syndrome

By analyzing ancient DNA, Dr. João Teixeira, ARC DECRA Fellow at The Australian National University (ANU), and colleagues recently uncovered what is believed to be the oldest case of Klinefelter syndrome.

A skeleton discovered in the medieval archaeological site of Torre Velha in North-eastern Portugal was radiocarbon dated to the 11^th century by scientists at the University of Coimbra, Portugal. The skeleton – an adult male, estimated to have been 25 years old at the time of death – was sent to the Australian research team for genetic analysis.

"We were immediately excited the first time we looked at the results," said Teixeira. "However, ancient DNA, is often degraded and of low quality and abundance, meaning we were initially cautious."

To overcome the limitations typically associated with ancient DNA analysis from osteological remains, the research team developed a novel Bayesian method that they “believe is a potentially efficient statistical way of analyzing fragmented DNA from a variety of sources (e.g., ancient DNA, cell-free DNA and DNA from forensic cases)”, they write in the paper.

"Given the fragile state of the DNA, we developed a new statistical method that could take into account the characteristics of ancient DNA, and our observations to confirm the diagnosis," Teixeira said.

DNA was extracted from the remains and genetically analyzed to map the degraded DNA fragments of the X and Y chromosomes against the reference human genome. Combining their analyses using the novel method, the researchers concluded that the individual’s karyotype was 47 XXY – meaning they carried an additional X chromosome. As the individual’s skeleton was well preserved, Teixeira and colleagues could also study its physical traits, which aligned with the diagnosis of Klinefelter syndrome (taller height than the average ancient Portuguese man, a larger bi-iliac width and malocclusion of the jaw and maxillary prognathism).

"In recent years, ancient DNA helped rewrite the history of worldwide human populations. Our study demonstrates it is now a valuable resource for biomedical research and the growing field of evolutionary medicine,” Dr. Bastien Llamas, associate professor and head of Molecular Anthropology at the Australian Centre for Ancient DNA, said.

Reference: Roca-Rada X, Tereso S, Rohrlach AB, et al. A 1000-year-old case of Klinefelter’s syndrome diagnosed by integrating morphology, osteology, and genetics. The Lancet. 2022;400(10353):691-692. doi: 10.1016/S0140-6736(22)01476-3.

This article is a rework of a press release issued by the Australian National University. Material has been edited for length and content.