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Constitutional de novo deletion CNV encompassing REST predisposes to diffuse hyperplastic perilobar nephroblastomatosis (HPLN)
  1. Zerin Hyder1,
  2. Adele Fairclough1,2,
  3. Mike Groom3,
  4. Joan Getty3,
  5. Elizabeth Alexander1,
  6. Elke M van Veen1,
  7. Guy Makin4,5,
  8. Chitra Sethuraman6,
  9. Vivian Tang7,
  10. D Gareth Evans1,
  11. Eamonn R Maher8,9,
  12. Emma R Woodward1
  1. 1 Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
  2. 2 NW Genomic Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
  3. 3 NW Genomic Laboratory Hub, Liverpool Women’s Hospital, Liverpool, UK
  4. 4 Department of Paediatric Oncology, Royal Manchester Children’s Hospital, Manchester, UK
  5. 5 Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
  6. 6 Department of Paediatric Histopathology, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
  7. 7 Department of Radiology, Royal Manchester Children’s Hospital, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
  8. 8 Department of Medical Genetics, University of Cambridge, Cambridge, Cambridgeshire, UK
  9. 9 Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, Cambridgeshire, UK
  1. Correspondence to Dr Emma R Woodward, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester M13 9WL, Greater Manchester, UK; Emma.Woodward{at}


Background Nephroblastomatosis is a recognised precursor for the development of Wilms tumour (WT), the most common childhood renal tumour. While the majority of WT is sporadic in origin, germline intragenic mutations of predisposition genes such as WT1, REST and TRIM28 have been described in apparently isolated (non-familial) WT.

Despite constitutional CNVs being a well-studied cause of developmental disorders, their role in cancer predisposition is less well defined, so that the interpretation of cancer risks associated with specific CNVs can be complex.

Objective To highlight the role of a constitutional deletion CNV (delCNV) encompassing the REST tumour suppressor gene in diffuse hyperplastic perilobar nephroblastomatosis (HPLN).

Methods/results Array comparative genomic hybridisation in an infant presenting with apparently sporadic diffuse HPLN revealed a de novo germline CNV, arr[GRCh37] 4q12(57,385,330–57,947,405)x1. The REST tumour suppressor gene is located at GRCh37 chr4:57,774,042–57,802,010.

Conclusion This delCNV encompassing REST is associated with nephroblastomatosis. Deletion studies should be included in the molecular work-up of inherited predisposition to WT/nephroblastomatosis. Detection of delCNVs involving known cancer predisposition genes can yield insights into the relationship between underlying genomic architecture and associated tumour risk.

  • child health
  • cytogenetics
  • genetic predisposition to disease
  • genetics
  • germ-line mutation

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  • Contributors ERW and ERM planned the study. AF, MG, JG, EA, EMvV, GM, CS, VT and ERW contributed to the acquisition, analysis and interpretation of the data. The manuscript was critically appraised and approved by all authors.

  • Funding ERW and DGE are supported by the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007). ERM is funded by a European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre) and the Cancer Research UK Cambridge Cancer Centre. The University of Cambridge has received salary support in respect of ERM from the NHS in the East of England through the Clinical Academic Reserve. Funding for the DECIPHER project was provided by the Wellcome Trust.

  • Competing interests None declared.

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