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Germline pathogenic SMARCA4 variants in neuroblastoma
  1. Leora Witkowski1,2,
  2. Kim E. Nichols3,
  3. Marjolijn Jongmans4,
  4. Nienke van Engelen5,
  5. Ronald R de Krijger5,6,
  6. Jennifer Herrera-Mullar7,
  7. Lieve Tytgat5,
  8. Armita Bahrami8,
  9. Helen Mar Fan9,10,
  10. Aimee L Davidson10,11,
  11. Thomas Robertson10,12,
  12. Michael Anderson13,
  13. Martin Hasselblatt14,
  14. Sharon E. Plon15,
  15. William D Foulkes16,17
  1. 1Core Molecular Diagnostic Laboratory, McGill University Health Centre, Montreal, Québec, Canada
  2. 2Department of Human Genetics, McGill University, Montreal, Québec, Canada
  3. 3Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, USA
  4. 4Department of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
  5. 5Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
  6. 6Department of Pathology, University Medical Centre Utrecht, Utrecht, The Netherlands
  7. 7Ambry Genetics Corp, Aliso Viejo, California, USA
  8. 8Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
  9. 9Genetic Health Queensland, The University of Queensland, Brisbane, Queensland, Australia
  10. 10Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
  11. 11QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  12. 12Pathology Queensland, Queensland Health, Brisbane, Queensland, Australia
  13. 13Invitae Corporation, San Francisco, California, USA
  14. 14Institute of Neuropathology, University Hospital Münster, Münster, Germany
  15. 15Department of Pediatrics/Hematology-Oncology, Baylor College of Medicine, Houston, Texas, USA
  16. 16Lady Davis Institute and Segal Cancer Centre, Sir Mortimer B Davis Jewish General Hospital, Montreal, Québec, Canada
  17. 17Research Institute of the McGill University Health Centre, Montreal, Québec, Canada
  1. Correspondence to Dr William D Foulkes, Lady Davis Institute and Segal Cancer Centre, Sir Mortimer B Davis Jewish General Hospital, Montreal H3T 1E2, Canada; william.foulkes{at}


Heterozygous germline pathogenic variants (GPVs) in SMARCA4, the gene encoding the ATP-dependent chromatin remodelling protein SMARCA4 (previously known as BRG1), predispose to several rare tumour types, including small cell carcinoma of the ovary, hypercalcaemic type, atypical teratoid and malignant rhabdoid tumour, and uterine sarcoma. The increase in germline testing of SMARCA4 in recent years has revealed putative GPVs affecting SMARCA4 in patients with other cancer types. Here we describe 11 patients with neuroblastoma (NBL), including 4 previously unreported cases, all of whom were found to harbour heterozygous germline variants in SMARCA4. Median age at diagnosis was 5 years (range 2 months–26 years); nine were male; and eight of nine cases had tumour location information in the adrenal gland. Eight of the germline variants were expected to result in loss of function of SMARCA4 (large deletion, truncating and canonical splice variants), while the remaining four were missense variants. Loss of heterozygosity of the wild-type SMARCA4 allele was found in all eight cases where somatic testing was performed, supporting the notion that SMARCA4 functions as a classic tumour suppressor. Altogether, these findings strongly suggest that NBL should be included in the spectrum of SMARCA4-associated tumours.

  • Genetic Predisposition to Disease
  • Genetic Testing
  • Germ-Line Mutation
  • Pediatrics
  • Sequence Analysis, DNA

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  • LW and KEN contributed equally.

  • Contributors LW and KN contributed equally to this paper. LW, KN, SP and WDF designed the study and contributed to manuscript preparation and editing. MJ, LT, NvE, JH-M, HM, ALD and MJA provided study patients. RRdK, AB, TR, MH performed pathology review on the cases. All authors critically reviewed and approved the final manuscript.

  • Funding ALD is supported by an Australian Government Research Training Program (RTP) Scholarship and a QIMR Berghofer HDC PhD Top Up Scholarship. Case identified via research was funded by Australian Genomics, NHMRC (grants GNT1113531 and GNT2000001) and the Australian Government’s Medical Research Future Fund. SEP is funded by the National Institutes of Health (grant 5 U01 HG006485). WDF is funded by the Canadian Institutes of Health Research (FDN-148390).

  • Competing interests MJ is a full-time, salaried employee of Invitae Corporation. JH-M is a full-time, salaried employee of Ambry Genetics. RRdK is a council member European Society of Pathology, unpaid. MJ is a board member of the SIOP Europe host genome working group, unpaid. SP is a member of the board of directors, American Society of Human Genetics, and a member of the scientific advisory panel, Baylor Genetics. LW is a consultant for PierianDx and Precision Rx-Dx Inc.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.