Ancient DNA Reveals 12,000-Year-Old Case of Rare Genetic Disorder
Researchers have identified genetic variants associated with a rare inherited growth disorder in two prehistoric individuals from southern Italy, marking the earliest known genetic diagnosis in humans.
An international research team led by the University of Vienna and Liège University Hospital Centre has identified genetic variants linked to a rare inherited growth disorder in two individuals who lived over 12,000 years ago. By combining ancient DNA analysis with modern clinical genetics, the researchers diagnosed the condition in two individuals buried together in southern Italy. Their findings, published in the New England Journal of Medicine, demonstrate that paleogenomics can now trace ancient population history and pinpoint rare genetic diseases in prehistoric humans.
The study focused on a double burial discovered in 1963 at Grotta del Romito in Calabria, Italy. The two individuals—"Romito 1," an adult female approximately 145 cm tall, and "Romito 2," an adolescent or young adult about 110 cm tall—were buried in an embrace. Romito 2 exhibited notably shortened limbs, consistent with a rare skeletal disorder called acromesomelic dysplasia, though bones alone could not confirm the diagnosis. Romito 1 was also shorter than average for that time period. Over the years, experts debated their sex, relationship, and whether a medical condition explained their statures.
To investigate further, scientists extracted ancient DNA from the petrous portion of the temporal bone in both skeletons, an area known for preserving genetic material. The results showed the two were first-degree relatives. The team then examined genes involved in bone growth and compared the detected variants with modern medical data. This collaborative effort brought together paleogenomics, clinical genetics, and physical anthropology, with researchers from the University of Vienna working alongside colleagues in Italy, Portugal, and Belgium.
Genetic testing revealed that both individuals were female and closely related, most likely a mother and daughter. In Romito 2, researchers found a homozygous mutation in the NPR2 gene, which plays a key role in bone development. This provided clear evidence of acromesomelic dysplasia, Maroteaux type—a very rare inherited disorder characterized by severe short stature and significant shortening of the limbs. Romito 1 carried a single altered copy of the same gene, associated with a milder form of short stature, explaining the difference in height between the two women.
Despite severe physical limitations, Romito 2 survived into adolescence or adulthood, suggesting sustained care within her community. Alfredo Coppa of Sapienza University of Rome, who also co-led the study, stated that her survival would have required sustained support from her group, including help with food and mobility in a challenging environment.
The findings underscore that rare genetic diseases are not limited to modern populations. Adrian Daly of Liège University Hospital Centre, a co-leader of the study, noted that rare genetic diseases are not a modern phenomenon but have been present throughout human history. Understanding their history may help in recognizing such conditions today.