A 12,000-Year-Old Case of NPR2-Related Acromesomelic Dysplasia

Ancient DNA (aDNA) techniques have revolutionized our understanding of human evolution and societal development but have not been used widely to study the genetic health of ancient individuals. Here we report the earliest genetic diagnosis of a monogenic, autosomal recessive disease in a 12,000-year-old Hunter-Gatherer (“Romito 2”) from a double burial in the Romito Cave, Italy. We established Romito 2 to be female and determined a close, first-degree biological relationship to the female Romito 1, with whom she was buried. Romito 2 exhibited a homozygous pathogenic variant (c.1801C>T; p.Arg601Cys) in the NPR2 gene, with 16x coverage at this locus. This finding was consistent with the skeletal features of the rare disease, acromesomelic dysplasia-Maroteaux type. Romito 1 was also short-statured in keeping with NPR2 heterozygosity, although aDNA quality and coverage were lower. This study establishes the earliest definitive genetic diagnosis of a rare disease, validating high-coverage aDNA approaches for identifying single-nucleotide variants in prehistoric remains from 12000 years ago. The survival of Romito 2 into late adolescence, despite severe physical limitations, strongly suggests the provision of significant social care within this ancient Hunter-Gatherer community, highlighting adaptive strategies for supporting individuals with severe physical limitations in prehistoric times.