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Purpose <p>Medulloblastoma (MB), a malignant cerebellar embryonal tumor, is predominantly sporadic, with rare familial cases linked to germline mutations in <i>SUFU</i>, <i>PTCH1</i>, <i>TP53</i>, and <i>APC</i>, primarily driving WNT and SHH molecular subtypes. Familial non-<i>WNT</i>/non-<i>SHH</i> MBs remain poorly understood, with limited genetic insights.</p> Methods <p>This study presents two siblings (11-year-old male, 16-year-old female) with non-<i>WNT</i>/non-<i>SHH</i> MBs. Whole exome sequencing (WES) was performed on tumor samples (MB1-T, MB2-T), peripheral blood (MB2-PB, parents), and analyzed for somatic/germline variants. Screening criteria excluded intronic/synonymous single nucleotide variants (SNVs) and common alleles.</p> Results <p>MB2 harbored somatic chromosome 17q gain (prognostic marker) and two deleterious <i>NF1</i> mutations (p.G2785V, p.N2788Y), absent in MB1. Germline analysis identified rare variants in <i>KYAT3</i>,<i> SPATA31A6</i>, and <i>CBWD6</i>, with potential roles in metabolic reprogramming (<i>KYAT3</i>) and genomic instability (<i>SPATA31A6</i>). No known MB predisposition syndromes or mutations were detected.</p> Conclusion <p>This first report of familial non-<i>WNT</i>/non-<i>SHH</i> MBs highlights novel somatic (<i>NF1</i>) and germline (<i>KYAT3</i>,<i> SPATA31A6</i>) variants, suggesting unexplored oncogenic mechanisms. The findings underscore the need for further research to elucidate drivers of non-<i>WNT</i>/non-<i>SHH</i> MBs and develop targeted therapies. WES proves critical in uncovering genetic underpinnings of rare familial MBs.</p>

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Non-WNT/non-SHH medulloblastoma in siblings: case report and literature review

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月20日

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  • Meng Huang,
  • Jian Li,
  • Bo Liu,
  • Yuxiang Liao,
  • Bin Wang,
  • Haipeng Liu,
  • Ying Liu,
  • Jie Zhao

摘要

Purpose

Medulloblastoma (MB), a malignant cerebellar embryonal tumor, is predominantly sporadic, with rare familial cases linked to germline mutations in SUFU, PTCH1, TP53, and APC, primarily driving WNT and SHH molecular subtypes. Familial non-WNT/non-SHH MBs remain poorly understood, with limited genetic insights.

Methods

This study presents two siblings (11-year-old male, 16-year-old female) with non-WNT/non-SHH MBs. Whole exome sequencing (WES) was performed on tumor samples (MB1-T, MB2-T), peripheral blood (MB2-PB, parents), and analyzed for somatic/germline variants. Screening criteria excluded intronic/synonymous single nucleotide variants (SNVs) and common alleles.

Results

MB2 harbored somatic chromosome 17q gain (prognostic marker) and two deleterious NF1 mutations (p.G2785V, p.N2788Y), absent in MB1. Germline analysis identified rare variants in KYAT3, SPATA31A6, and CBWD6, with potential roles in metabolic reprogramming (KYAT3) and genomic instability (SPATA31A6). No known MB predisposition syndromes or mutations were detected.

Conclusion

This first report of familial non-WNT/non-SHH MBs highlights novel somatic (NF1) and germline (KYAT3, SPATA31A6) variants, suggesting unexplored oncogenic mechanisms. The findings underscore the need for further research to elucidate drivers of non-WNT/non-SHH MBs and develop targeted therapies. WES proves critical in uncovering genetic underpinnings of rare familial MBs.