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CDKN1C hyperexpression in two patients with severe growth failure and microdeletions affecting the paternally inherited KCNQ1OT1:TSS-DMR
  1. Kaori Hara-Isono1,2,
  2. Kazuki Yamazawa3,
  3. Satsuki Tanaka4,
  4. Eriko Nishi5,
  5. Maki Fukami1,
  6. Masayo Kagami1
  1. 1 Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
  2. 2 Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
  3. 3 Medical Genetics Center, National Hospital Organisation Tokyo Medical Center, Tokyo, Japan
  4. 4 Department of Diabetes and Endocrinology, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan
  5. 5 Department of Medical Genetics, Osaka Women's and Children's Hospital, Izumi, Japan
  1. Correspondence to Dr Masayo Kagami, Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; kagami-ms{at}


Background Two imprinting control centres, H19/IGF2:IG-differentialy methylated region (DMR) and KCNQ1OT1:TSS-DMR, reside on chromosome 11p15.5. Paternal deletions involving the KCNQ1OT1:TSS-DMR result in variable phenotypes, namely, normal phenotype, Silver-Russel syndrome (SRS) and fetal demise. However, expression analyses for CDKN1C in these patients are very limited.

Cases Patient 1 (adult woman) and patient 2 (boy in early childhood) showed prenatal and postnatal growth failure and clinical suspicion of SRS.

Molecular analyses Both patients showed hypermethylation of the KCNQ1OT1:TSS-DMR caused by the paternal heterozygous de novo deletions involving the KCNQ1OT1:TSS-DMR, but not including CDKN1C enhancers. The deletion sizes were 5 kb and 12 kb for patients 1 and 2, respectively. CDKN1C gene expressions in immortalised leucocytes of both patients were increased compared with those of controls.

Conclusion Paternal deletions involving the KCNQ1OT1:TSS-DMR, but not including CDKN1C enhancers, disrupt KCNQ1OT1 expression, strongly activate CDKN1C expression and consequently cause severe growth failure.

  • epigenomics
  • human genetics

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  • Contributors KH-I performed the molecular analyses and wrote the manuscript. ST and EN provided detailed clinical data and materials for molecular analyses. KY and MF supervised the study. MK designed the project, wrote the manuscript and gave the final approval of the version to be published.

  • Funding This work was supported by grants from the National Center for Child Health and Development (2019B-4), the Japan Agency for Medical Research and Development (AMED) (20ek0109373h0003) and the Takeda Science Foundation.

  • Competing interests None declared.

  • 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.