Whole-exome sequencing of the mummified remains of Cangrande della Scala (1291\u20131329 CE) indicates the first known case of late-onset Pompe disease

Barbara Iadarola,Massimo Delledonne,Valentina Zaro,Martina Lari,David Caramelli,Alessandro Salviati,Leonardo Latella,Alessandra Modi,Cristina Beltrami,Chiara Degli Esposti,Marzia Rossato,Ettore Napione,Denise Lavezzari

doi:10.1038/s41598-021-00559-1

Barbara Iadarola, Massimo Delledonne + Show 11 more

Open Access

https://doi.org/10.1038/s41598-021-00559-1

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Journal: Scientific Reports	Publication Date: Oct 26, 2021
Citations: 2	License type: open-access

Affiliation: University of Verona, University of Florence

Abstract

Mummified remains of relevant historical figures are nowadays an important source of information to retrace data concerning their private life and health, especially when historical archives are not available. Next-generation-sequencing was proved to be a valuable tool to unravel the characteristics of these individuals through their genetic heritage. Using the strictest criteria currently available for the validation of ancient DNA sequences, whole-genome and whole-exome sequencing were generated from the mummy remains of an Italian nobleman died almost 700 years ago, Cangrande della Scala. While its genome sequencing could not yield sufficient coverage for in depth investigation, exome sequencing could overcome the limitations of this approach to achieve significantly high coverage on coding regions, thus allowing to perform the first extensive exome analysis of a mummy genome. Similar to a standard “clinical exome analysis” conducted on modern DNA, an in-depth variant annotation, high-quality filtering and interpretation was performed, leading to the identification of a genotype associated with late-onset Pompe disease (glycogen storage disease type II). This genetic diagnosis was concordant with the limited clinical history available for Cangrande della Scala, who likely represents the earliest known case of this autosomal recessive metabolic disorder.

Highlights

DNA is naturally broken down into fragments after death and is degraded to single nucleotides, but sequence information can be recovered from samples that are hundreds of thousands of years o ld[1]
DNA extracted from the mummified remains of Cangrande della Scala was used for three exploratory whole-genome sequencing (WGS) experiments
We have described the successful clinical analysis of a 700-year-old human mummy by whole-exome sequencing (WES) and demonstrated that exome enrichment applied to ancient human DNA can lead to a genetic diagnosis that may help to support historical data

Summary

Introduction

DNA is naturally broken down into fragments after death and is degraded to single nucleotides, but sequence information can be recovered from samples that are hundreds of thousands of years o ld[1]. An interesting case study is Cangrande della Scala (1291–1329 CE), lord of Verona from 1311 to 1329, a great military commander and politician who brought neighboring cities under his control to form a “kingdom” of the Venetian hinterland spanning from Verona to Treviso Verifiable data about his private life and health are scarce because the Scaliger family archives were destroyed, forcing historians to rely on less reliable sources that may be influenced by positive or negative bias. Cangrande della Scala was interred in a marble tomb that promoted mummification His remains were exhumed in 2004 for scientific analysis by a multidisciplinary team of researchers, revealing the presence of digitalis in his well-preserved o rgans[2,3]. The clinical phenotype of this disease is consistent with data from the historical records, suggesting that Cangrande della Scala is the earliest known case of this prototypic lysosomal storage disorder

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