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Genotype-phenotype correlations
Original research
Genotypes and phenotypes of DNM1 encephalopathy
  1. Jeehyun Kim1,
  2. Lip-Yuen Teng2,
  3. Bilal Shaker3,
  4. Dokyun Na3,
  5. Hyun Yong Koh4,
  6. Soon Sung Kwon5,
  7. Joon Soo Lee1,6,7,
  8. Heung Dong Kim1,6,7,
  9. Hoon-Chul Kang1,6,7,
  10. Se Hee Kim1,6,7
  1. 1 Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
  2. 2 Paediatric Neurology, Hospital Tunku Azizah, Kuala Lumpur, Malaysia
  3. 3 Department of Biomedical Engineering, Chung-Ang University, Seoul, Korea
  4. 4 F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, USA
  5. 5 Department of Laboratory Medicine, Yonsei University College of Medicine, Seodaemun-gu, Korea
  6. 6 Pediatric Neurology, Department of Pediatrics, Severance Children's Hospital, Seoul, Korea
  7. 7 Epilepsy Research Institute, Yonsei University College of Medicine, Epilepsy Research Institute, Seoul, Korea
  1. Correspondence to Dr Hoon-Chul Kang; hipo0207{at}yuhs.ac; Professor Se Hee Kim, Divison of Pediatric Neurology, Department of Pediatrics, Severance Children’s Hospital, Yonsei University College of Medicine, Epilepsy Research Institute, Seoul 03722, Korea; SEHEEKIM{at}yuhs.ac

Abstract

Background Variants in the dynamin-1 (DNM1) gene typically cause synaptopathy, leading to developmental and epileptic encephalopathy (DEE). We aimed to determine the genotypic and phenotypic spectrum of DNM1 encephalopathy beyond DEE.

Methods Electroclinical phenotyping and genotyping of patients with a DNM1 variant were conducted for patients undergoing next-generation sequencing at our centre, followed by a systematic review.

Results Six patients with heterozygous DNM1 variants were identified in our cohort. Three had a typical DEE phenotype characterised by epileptic spasms, tonic seizures and severe-to-profound intellectual disability with pathogenic variants located in the GTPase or middle domain. The other three patients had atypical phenotypes of milder cognitive impairment and focal epilepsy. Genotypically, two patients with atypical phenotypes had variants located in the GTPase domain, while the third patient had a novel variant (p.M648R) in the linker region between pleckstrin homology and GTPase effector domains. The third patient with an atypical phenotype showed normal development until he developed febrile status epilepticus. Our systematic review on 55 reported cases revealed that those with GTPase or middle domain variants had more severe intellectual disability (p<0.001) and lower functional levels of ambulation (p=0.001) or speech and language (p<0.001) than the rest.

Conclusion DNM1-related phenotypes encompass a wide spectrum of epilepsy and neurodevelopmental disorders, with specific variants underlying different phenotypes.

  • epilepsy
  • developmental
  • child health

Data availability statement

Data are available on reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request.

https://doi.org/10.1136/jmg-2023-109233

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    Data availability statement

    Data are available on reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request.

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    Footnotes

    • Twitter @she33435@gmail.com

    • JK and L-YT contributed equally.

    • Contributors JK: Data curation. L-YT: Methodology, data curation, formal analysis, visualisation, writing—original draft, review and editing. BS, DN and HYK: Visualisation and writing. SSK: Writing—review and editing. H-CK, JSL and HDK: Supervision and editing. SHK: Guarantor. Conceptualisation, methodology, validation, supervision (lead) and writing—review and editing. All authors reviewed the results and approved the final version of the manuscript.

    • Funding This study was supported by Severance Hospital Yonsei University, Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education NRF-2022R1A2C1012522; a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea, grant number HI21C1659; and the Team Science Award of Yonsei University College of Medicine 6-2021-0007.

    • 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.