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<p>Multiple osteochondromas (MO) is a rare bone disease with variable manifestations that make it difficult to distinguish from phenotypically similar diseases, both morphologically and radiologically. As a monogenic disorder associated with mutations in <i>EXT1</i> or <i>EXT2</i>, ancient DNA analysis can provide genetically confirmed diagnoses and insights into the pathogenesis of suspected cases. To further investigate a previously reported suspected MO case from Qing-period Shandong, China, we generated ancient whole-exome sequencing data from the individual’s petrous bone, yielding a mean sequencing coverage of 27.172×. We identified a pathogenic heterozygous mutation in the ligand-binding site Rossmann-2 subdomain of <i>EXT1</i> (c.791T &gt; C; p.Leu264Pro) with a sequencing depth of 17×, a mutation also found in an unrelated modern Latin American patient. Additionally, by predicting and analyzing the 3D structure of the EXT1 protein, we detected structural and functional damage. Our findings expand the known spectrum of <i>EXT1</i> mutations and enhance the comprehensive genotype–phenotype map of rare MO, providing insights into its genetic pathology from a historical perspective. Furthermore, this research expands the understanding of disease landscapes in Northern China, both paleopathologically and paleogenetically.</p>

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High-coverage paleo-genome research identifies a pathogenic mutation on EXT1 in a Qing-period Chinese individual with multiple osteochondromas

  • 期刊论文

  • 发表日期：

    2026年7月25日

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  • Bangyan Wang,
  • Haodong Chen,
  • Fanhao Xi,
  • Haoquan Bao,
  • Hetong Wen,
  • Panxin Du,
  • Chenshuang Sun,
  • Jianxue Xiong,
  • Baoshuai Zhang,
  • Xin Chang,
  • Yawei Zhou,
  • Chuan-Chao Wang,
  • Shaoqing Wen

摘要

Multiple osteochondromas (MO) is a rare bone disease with variable manifestations that make it difficult to distinguish from phenotypically similar diseases, both morphologically and radiologically. As a monogenic disorder associated with mutations in EXT1 or EXT2, ancient DNA analysis can provide genetically confirmed diagnoses and insights into the pathogenesis of suspected cases. To further investigate a previously reported suspected MO case from Qing-period Shandong, China, we generated ancient whole-exome sequencing data from the individual’s petrous bone, yielding a mean sequencing coverage of 27.172×. We identified a pathogenic heterozygous mutation in the ligand-binding site Rossmann-2 subdomain of EXT1 (c.791T > C; p.Leu264Pro) with a sequencing depth of 17×, a mutation also found in an unrelated modern Latin American patient. Additionally, by predicting and analyzing the 3D structure of the EXT1 protein, we detected structural and functional damage. Our findings expand the known spectrum of EXT1 mutations and enhance the comprehensive genotype–phenotype map of rare MO, providing insights into its genetic pathology from a historical perspective. Furthermore, this research expands the understanding of disease landscapes in Northern China, both paleopathologically and paleogenetically.