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  • Whole-exome sequencing reveals causative genetic variants for several overgrowth syndromes in molecularly negative Beckwith-Wiedemann spectrum

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Epigenetics
Short report
Whole-exome sequencing reveals causative genetic variants for several overgrowth syndromes in molecularly negative Beckwith-Wiedemann spectrum
  1. Ken Higashimoto1,
  2. Feifei Sun1,2,
  3. Eri Imagawa3,
  4. Ken Saida4,
  5. Noriko Miyake4,5,
  6. Satoshi Hara1,
  7. Hitomi Yatsuki1,
  8. Musashi Kubiura-Ichimaru1,
  9. Atsushi Fujita4,
  10. Takeshi Mizuguchi4,
  11. Naomichi Matsumoto4,
  12. Hidenobu Soejima1
  1. 1 Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Saga University Faculty of Medicine, Saga, Japan
  2. 2 Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China
  3. 3 Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan
  4. 4 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  5. 5 Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
  1. Correspondence to Professor Hidenobu Soejima, Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Saga University Faculty of Medicine, Saga, 849-8501, Japan; soejimah{at}cc.saga-u.ac.jp

Abstract

Background Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder caused by (epi)genetic alterations at 11p15. Because approximately 20% of patients test negative via molecular testing of peripheral blood leukocytes, the concept of Beckwith-Wiedemann spectrum (BWSp) was established to encompass a broader cohort with diverse and overlapping phenotypes. The prevalence of other overgrowth syndromes concealed within molecularly negative BWSp remains unexplored.

Methods We conducted whole-exome sequencing (WES) on 69 singleton patients exhibiting molecularly negative BWSp. Variants were confirmed by Sanger sequencing or quantitative genomic PCR. We compared BWSp scores and clinical features between groups with classical BWS (cBWS), atypical BWS or isolated lateralised overgrowth (aBWS+ILO) and overgrowth syndromes identified via WES.

Results Ten patients, one classified as aBWS and nine as cBWS, showed causative gene variants for Simpson-Golabi-Behmel syndrome (five patients), Sotos syndrome (two), Imagawa-Matsumoto syndrome (one), glycosylphosphatidylinositol biosynthesis defect 11 (one) or 8q duplication/9p deletion (one). BWSp scores did not distinguish between cBWS and other overgrowth syndromes. Birth weight and height in other overgrowth syndromes were significantly larger than in aBWS+ILO and cBWS, with varying intergroup frequencies of clinical features.

Conclusion Molecularly negative BWSp encapsulates other syndromes, and considering both WES and clinical features may facilitate accurate diagnosis.

  • Genetic Diseases, Inborn
  • Whole Exome Sequencing

Data availability statement

All data supporting the conclusions of this study, except for CNVs and exome sequencing, are presented within the article and its supplementary material. The authors are willing to share the data in this study upon request.

https://doi.org/10.1136/jmg-2023-109621

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    Data availability statement

    All data supporting the conclusions of this study, except for CNVs and exome sequencing, are presented within the article and its supplementary material. The authors are willing to share the data in this study upon request.

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    Footnotes

    • KH, FS, EI and KS are joint first authors.

    • KH, FS, EI and KS contributed equally.

    • Contributors Conceptualisation: HS; data curation: KH, FS, KS, HS; formal Analysis: KH, EI, KS, HY, AF, TM, NoM; funding acquisition: HK, SH, FS, AF, TM, NMa, HS; project administration: HS; resources: KH, HS; writing—original draft: KH, HS; writing—review and editing: KH, EI, KS, SH, MK-I, NMa, HS.

    • Funding This study was supported in part by the following grants: the Japan Society for the Promotion of Science (JSPS) KAKENHI grant numbers JP21K19451 (HS), JP20H03643 (HS), JP23K07251 (KH), JP23K05592 (SH), JP22KK0111 (SH), JP22H03047 (NoM), JP23H02877 (TM), JP22K15901 (AF), and Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics (SH); the Japan Agency for Medical Research and Development (AMED) under grant numbers JP22ek0109587 (HS), JP23ek0109674 (HS and NMa), JP23ek0109549 (NMa), JP23ek0109617 (NMa), JP23ek0109648 (NMa) and JP23ek0109672 (HS); the Takeda Science Foundation (NMa); the Ministry of Health, Labour and Welfare (MHLW) Program grant number 23FC1052 (HS); Liaoning Province Medical-Industrial Crossover Joint Fund (2022-YGJC-55) (FS); Young and Middle-aged Scientific and Technological Innovation Talent Support Project of Shenyang City (RC210226) (FS); 345 Talent Project (M0282) (FS); and The Second Clinical College of China Medical University Educational Innovation (Open) Project (SJKF-2022YB04) (FS).

    • 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.