De novo FRMD5 Missense Variants in Patients with Childhood-Onset Ataxia, Prominent Nystagmus, and Seizures

Ignacio J. Keller Sarmiento, Bernabe I. Bustos, Joanna Blackburn, Nicholas E.F. Hac, Maura Ruzhnikov, Matthea Monroe, Rebecca J. Levy, Lisa Kinsley, Megan Li, Vincenzo Silani, Steven J. Lubbe, Dimitri Krainc, Niccolò E. Mencacci*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background: FRMD5 variants were recently identified in patients with developmental delay, ataxia, and eye movement abnormalities. Objectives: We describe 2 patients presenting with childhood-onset ataxia, nystagmus, and seizures carrying pathogenic de novo FRMD5 variants. Weighted gene co-expression network analysis (WGCNA) was performed to gain insights into the function of FRMD5 in the brain. Methods: Trio-based whole-exome sequencing was performed in both patients, and CoExp web tool was used to conduct WGCNA. Results: Both patients presented with developmental delay, childhood-onset ataxia, nystagmus, and seizures. Previously unreported findings were diffuse choreoathetosis and dystonia of the hands (patient 1) and areas of abnormal magnetic resonance imaging signal in the white matter (patient 2). WGCNA showed that FRMD5 belongs to gene networks involved in neurodevelopment and oligodendrocyte function. Conclusions: We expanded the phenotype of FRMD5-related disease and shed light on its role in brain function and development. We recommend including FRMD5 in the genetic workup of childhood-onset ataxia and nystagmus.

Original languageEnglish (US)
Pages (from-to)1231-1236
Number of pages6
JournalMovement Disorders
Volume39
Issue number7
DOIs
StatePublished - Jul 2024

Funding

I.J.K.S. is supported by the Align Science Across Parkinson's (ASAP) Global Parkinson's Genetics Program (GP2). ORCID 0000\u20100003\u20100979\u20106001. N.E.M. receives NIH funding (1K08NS131581) and is supported by the Align Science Across Parkinson's (ASAP) Global Parkinson's Genetics Program (GP2). He is a member of the steering committee of the PD GENEration study for which he receives an honorarium from the Parkinson's Foundation. ORCID: 0000\u20100003\u20103383\u20109665. V.S. received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, Liquidweb S.r.l., Novartis Pharma AG, and Zambon Biotech SA. He receives or has received research support from the Italian Ministry of Health, AriSLA, and E\u2010Rare Joint Transnational Call. He is on the editorial boards of , , , , and . ORCID: 000 0002 7698 3854. D.K. is the founder and scientific advisory board chair of Lysosomal Therapeutics Inc. and Vanqua Bio. D.K. serves on the scientific advisory boards of the Silverstein Foundation, Intellia Therapeutics, AcureX, and Prevail Therapeutics and is a Venture Partner at OrbiMed. R.J.L. is a consultant for Tome Bio. All authors declare that they do not have competing interests. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration European Neurology American Journal of Neurodegenerative Diseases Frontiers in Neurology Exploration of Neuroprotective Therapy

Keywords

  • FRMD5
  • ataxia
  • genetics
  • nystagmus
  • weighted gene co-expression network analysis

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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