By examining two skeletons that were more than 12,000 years old, researchers were able to diagnose a rare hereditary growth disorder from prehistoric times. The analysis of ancient DNA in combination with modern clinical genetics showed a close relationship between the two individuals and thus provided new insights into genetic diseases of the past.
The starting point for the investigation was a double grave from the late Paleolithic period in the Grotta del Romito in southern Italy, which was discovered in 1963 and has been the subject of research ever since. Striking skeletal features and the unusual manner of burial led to discussions for decades about the relationship between the two buried people and the causes of their small heights.
An extraordinary double grave
The two people were buried in an embrace: “Romito 2”, a teenager who had previously been incorrectly classified as male, had significantly shortened arms and legs and was lying in the arms of “Romito 1”, an adult woman. There was no evidence of violence on the skeletons. Romito 2’s height is estimated to be around 110 centimeters, which is consistent with a rare bone growth disorder (acromesomelic dysplasia). However, this diagnosis could not be confirmed based on the bones alone. At around 145 centimeters, Romito 1 was also smaller than usual for that time. For decades, researchers discussed the gender and relationships of those buried and the question of whether there could be a common cause behind the short stature.
A research team led by the University of Vienna and the University Hospital of Liège now investigated this question using genetic analyses. To do this, the researchers used DNA from the temporal bone of the temporal bone – a region in which genetic material is particularly well preserved. The evaluation showed that the two individuals were closely related to each other. The researchers then examined genes that are important for bone growth and compared the variants they found with current clinical data.
Earliest genetic diagnosis in humans
The genetic analyzes initially showed that both individuals were female and first-degree related – most likely mother and daughter. In Romito 2, the researchers also found two modified copies of the NPR2 gene, which plays a central role in bone growth. This confirmed the diagnosis of Maroteaux-type acromesomelic dysplasia – a very rare hereditary disease that leads to severe short stature and significantly shortened limbs. Romito 1 only carried a modified copy of the same gene, which is associated with a milder form of short stature.
Ron Pinhasi from the University of Vienna, co-leader of the study, says: “By analyzing ancient DNA, we can now specifically search for genetic changes in people from prehistory. This makes it possible to understand how far back rare genetic diseases go back in human history – and we may also discover previously unknown variants in the process.” Daniel Fernandes from the University of Coimbra, lead author of the study, adds: “The fact that both people were female and closely related makes this burial a kind of genetic family history. The milder short stature of the older woman can probably be explained by the fact that she only carried one altered gene copy. This way we see how the same genetic change had different effects within a prehistoric family.” The results are also important for today’s medicine, emphasizes Adrian Daly from the University Hospital of Liège, also co-leader of the study: “Rare genetic diseases are not a modern phenomenon, but have been with humanity for a very long time. If we understand their history better, we can recognize such diseases more easily today.”
It is also important to take the social circumstances associated with the findings into account. Despite severe physical limitations, Romito 2 reached adolescence or perhaps even adulthood. This suggests that she received support from her community over a long period of time. Alfredo Coppa from the Sapienza University of Rome, also co-leader of the study, says: “We assume that their survival was only possible because their group provided them with constant support – for example in obtaining food and moving around in a demanding environment.”
Source: Theresa Bittermann, University of Vienna;
Article: New England Journal of Medicine: Pinhasi et. al. (2026): A 12,000-Year-Old Case of NPR2-Related Acromesomelic Dysplasia; DOI: 10.1056/NEJMc2513616