Ancient DNA diagnoses rare genetic disorder in 12,000-year-old Ice Age family

Ancient DNA reveals rare genetic disorder in Ice Age family

Researchers have diagnosed a rare genetic growth disorder in two people buried together in Italy more than 12,000 years ago. The discovery, published in the New England Journal of Medicine, marks the earliest known genetic diagnosis in humans.

An international team led by the University of Vienna and Lige University Hospital Centre combined ancient DNA analysis with modern clinical genetics. They studied skeletons from a famous Upper Paleolithic burial site called Grotta del Romito, discovered in 1963.

A mysterious double burial

The two individuals were buried in an embrace. One skeleton, known as Romito 2, had notably shortened limbs and was only about 110 cm (3'7") tall.

The other, Romito 1, was also shorter than average for the period at roughly 145 cm (4'9"). For decades, scientists debated their relationship and whether a medical condition explained their stature.

To solve the mystery, researchers extracted ancient DNA from the petrous bone of both skeletons. This bone is known for preserving genetic material well over millennia.

Genetic diagnosis confirms rare disease

The DNA analysis revealed both individuals were female and were first-degree relatives, most likely a mother and daughter. This finding alone recontextualized the burial as a familial case.

In the younger woman, Romito 2, researchers found a homozygous mutation in the NPR2 gene, which is crucial for bone development. This provided clear evidence of acromesomelic dysplasia, Maroteaux type.

This is a very rare inherited disorder characterized by:

• Severe short stature
• Significant shortening of the limbs

Romito 1, the older woman, carried only a single altered copy of the same gene. This heterozygous pattern is associated with a milder form of short stature, explaining the height difference between them.

Rare diseases are not a modern phenomenon

The study demonstrates that paleogenomics can now trace specific genetic diseases deep into human prehistory. "By applying ancient DNA analysis, we can now identify specific mutations in prehistoric individuals," said co-lead author Ron Pinhasi of the University of Vienna.

He explained this helps establish how far back rare genetic conditions existed and may uncover previously unknown variants. First author Daniel Fernandes of the University of Coimbra noted the discovery shows how the same gene affected members of a prehistoric family differently.

"Rare genetic diseases are not a modern phenomenon but have been present throughout human history," said co-leader Adrian Daly of Lige University Hospital Centre. "Understanding their history may help recognising such conditions today."

Evidence of prehistoric care and support

A key implication of the finding is social. Despite the serious physical challenges of her condition, Romito 2 lived into adolescence or early adulthood.

Her survival in a challenging Ice Age environment suggests she received consistent support from her community. "We believe her survival would have required sustained support from her group, including help with food and mobility," said co-lead author Alfredo Coppa of Sapienza University of Rome.

The research team included scientists from Austria, Italy, Portugal, and Belgium. Their work bridges the fields of paleogenomics, clinical genetics, and physical anthropology to rewrite a small but significant chapter of human history.