Ancient DNA reveals 12,000-year-old case of rare genetic disease

Researchers led by the University of Vienna and Liège University Hospital Centre have identified genetic variants associated with a rare inherited growth disorder in two prehistoric individuals who lived more than 12,000 years ago. Using ancient DNA analysis and modern clinical genetics, they diagnosed the condition in a mother and daughter buried together in southern Italy. Published in the New England Journal of Medicine, the study shows that paleogenomics can now reconstruct ancient population history and diagnose rare genetic diseases in prehistoric individuals.

The discovery builds on a reanalysis of a well-known Upper Paleolithic burial discovered in 1963 at Grotta del Romito in southern Italy, which has long puzzled researchers. Unusual skeletal features and the circumstances of the burial raised longstanding questions about the relationship between the individuals and the medical reasons for their short stature.

A remarkable double burial raises questions

The two were interred together in an embrace. "Romito 2", an adolescent with pronounced limb shortening, previously assumed to be male, lay in the arms of "Romito 1", thought to be an adult female. No signs of trauma were observed. Romito 2 had an estimated height of about 110 cm, consistent with a rare skeletal growth disorder known as acromesomelic dysplasia, though this could not be confirmed solely from bones. Romito 1 was also shorter – about 145 cm –than average for the period. For decades, researchers debated their gender, relationship, and the possibility of a common cause of their short stature.

About the study

The team analysed ancient DNA extracted from the petrous part of the temporal bone of both individuals, a region known for preserving genetic material well. Genetic analysis established a first-degree relationship. The researchers then screened genes associated with skeletal growth and compared the identified variants with modern clinical data. This interdisciplinary approach, combining paleogenomics, clinical genetics, and physical anthropology, involved an international team from the University of Vienna and collaborators in Italy, Portugal, and Belgium.

Earliest genetic diagnosis in humans

The analysis showed that both individuals were female and first-degree relatives, most likely a mother and daughter. In Romito 2, researchers identified a homozygous variant in the NPR2 gene, which is essential for bone growth. This confirmed a diagnosis of acromesomelic dysplasia, Maroteaux type — a very rare inherited disorder characterized by severe short stature and marked shortening of the limbs. Genetic data from Romito 1 indicate that she carried one altered copy of the same gene, a condition associated with milder short stature.

Rare diseases in human history

Ron Pinhasi, University of Vienna, who co-led the study says: "By applying ancient DNA analysis, we can now identify specific mutations in prehistoric individuals. This helps establish how far back rare genetic conditions existed and may also uncover previously unknown variants." Daniel Fernandes of the University of Coimbra, first author of the study, adds: "Identifying both individuals as female and closely related turns this burial into a familial genetic case. The older woman's milder short stature likely reflects a heterozygous mutation, showing how the same gene affected members of a prehistoric family differently." Clinically, the results highlight the deep history of rare diseases. Adrian Daly of Liège University Hospital Centre, a co-leader of the study, notes: "Rare genetic diseases are not a modern phenomenon but have been present throughout human history. Understanding their history may help recognising such conditions today."

Evidence of social care

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, says: "We believe her survival would have required sustained support from her group, including help with food and mobility in a challenging environment."

Summary

• Ancient DNA analysis revealed that two individuals buried together in southern Italy were closely related — most likely mother and daughter.
• In the younger individual, two altered copies of the NPR2 gene confirmed acromesomelic dysplasia (Maroteaux type), a condition marked by severe short stature and pronounced limb shortening; the older individual carried one altered copy linked to milder short stature.
• The findings show that rare genetic diseases were already present in prehistoric populations and can now be studied using paleogenomics.
• The younger individual's survival despite severe physical limitations suggests sustained care and social support within her community.