Millennium-old pathogenic Mendelian mutation discovery for multiple osteochondromas from a Gaelic Medieval graveyard

Abstract

Only a limited number of genetic diseases are diagnosable in archaeological individuals and none have had causal mutations identified in genome-wide screens. Two individuals from the Gaelic Irish Medieval burial ground of Ballyhanna, Co. Donegal, showed evidence of bone tumours consistent with the autosomal dominant condition multiple osteochondromas. Genome sequencing of the earlier individual uncovered a missense mutation in the second exon of EXT1 , a specific lesion that has been identified in several modern patients. The later individual lacked this but displayed a novel frameshift mutation leading to a premature stop codon and loss of function in the same gene. These molecular confirmations of a paleopathological diagnosis within a single rural ancient context are surprisingly disjunct, given the observation of clusters of this disease in modern isolated populations and a de novo mutation rate of only 10%.

The Missing Piece of the Puzzle: Unveiling the Role of PTPN11 Gene in Multiple Osteochondromas in a Large Cohort Study

“…The identification of OCs through imaging studies such as X-rays or MRIs typically eliminates the need for differential diagnoses, and the presence of two or more OCs is sufficient for the diagnosis of MO according to clinical criteria [3]. The specificity and clear clinical findings of MO even make it possible to diagnose the disease by sequencing ancient DNA samples [4]. Despite the distinctive clinical features of MO, some families with MO still face challenges in obtaining a molecular diagnosis.…”

The value of exomes across the ages

“…Does genome sequencing have any value in archaeology? This paper by Jackson et al suggests so [15]. Two adult male individuals buried in a Medieval graveyard at Ballyhanna, near the town of Ballyshannon in Co. Donegal, Ireland, displayed multiple bony tumours suggestive of multiple osteochondromas, a rare, autosomal dominant bone condition.…”