2. Academic Validation
  3. Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy

Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy

  • Am J Hum Genet. 2021 Jan 7;108(1):176-185. doi: 10.1016/j.ajhg.2020.10.017.
Andrew E Fry 1,  Christopher Marra 2,  Anna V Derrick 3,  William O Pickrell 4,  Adam T Higgins 3,  Johann Te Water Naude 5,  Martin A McClatchey 6,  Sally J Davies 7,  Kay A Metcalfe 8,  Hui Jeen Tan 9,  Rajiv Mohanraj 10,  Shivaram Avula 11,  Denise Williams 12,  Lauren I Brady 13,  Ronit Mesterman 13,  Mark A Tarnopolsky 13,  Yuehua Zhang 14,  Ying Yang 14,  Xiaodong Wang 15,  Genomics England Research Consortium 16,  Mark I Rees 17,  Mitchell Goldfarb 2,  Seo-Kyung Chung 18
Affiliations

Affiliations

  • 1 Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK. Electronic address: fryae@cardiff.ac.uk.
  • 2 Department of Biological Sciences, Hunter College of City University, 695 Park Avenue, New York, NY 10065, USA; Program in Biology, Graduate Center of City University, 365 Fifth Avenue, New York, NY 10016, USA.
  • 3 Neurology and Molecular Neuroscience Research, Institute of Life Science, Swansea University Medical School, Swansea University, Swansea SA2 8PP, UK.
  • 4 Neurology and Molecular Neuroscience Research, Institute of Life Science, Swansea University Medical School, Swansea University, Swansea SA2 8PP, UK; Neurology department, Morriston Hospital, Swansea Bay University Hospital Health Board, Swansea SA6 6NL, UK.
  • 5 Paediatric Neurology, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK.
  • 6 Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
  • 7 Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK.
  • 8 Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust and Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.
  • 9 Department of Paediatric Neurology, Royal Manchester Children's Hospital, Oxford Road, Manchester M13 9WL, UK.
  • 10 Department of Neurology, Salford Royal Hospital NHS Foundation Trust, Stott Lane, Salford M6 8HD, UK.
  • 11 Department of Radiology, Alder Hey Children's NHS Foundation Trust, Eaton Road, Liverpool L12 2AP, UK.
  • 12 West Midlands Regional Genetics Service, Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
  • 13 Department of Paediatrics, McMaster University, 1200 Main St. W., Hamilton, ON L8N 3Z5, Canada.
  • 14 Department of Pediatrics, Peking University First Hospital, Xicheng District, Beijing 100034, China.
  • 15 Cipher Gene Ltd, Beijing, China.
  • 16 Genomics England, London EC1M 6BQ, UK.
  • 17 Neurology and Molecular Neuroscience Research, Institute of Life Science, Swansea University Medical School, Swansea University, Swansea SA2 8PP, UK; Faculty of Medicine and Health, Camperdown, University of Sydney, NSW 2006, Australia.
  • 18 Neurology and Molecular Neuroscience Research, Institute of Life Science, Swansea University Medical School, Swansea University, Swansea SA2 8PP, UK; Kids Neuroscience Centre, Kids Research, Children Hospital at Westmead, Sydney, NSW 2145, Australia; Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, NSW 2050, Australia.
PMID: 33245860 DOI: 10.1016/j.ajhg.2020.10.017
Abstract

Fibroblast Growth Factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Nav) channels in the brain and Other tissues. FHF dysfunction has been linked to neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome Sequencing identified hemi- and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating Nav channel function.

Keywords

FGF13; FHF2; X linked; developmental and epileptic encephalopathy; epilepsy; epileptic encephalopathy; infantile onset; voltage-gated sodium channel.

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