Rare dysfunctional SCN2A variants are associated with malformation of cortical development

Jérôme Clatot; Christopher H Thompson; Susan Sotardi; Jinan Jiang; Marina Trivisano; Simona Balestrini; D Isum Ward; Natalie Ginn; Brunetta Guaragni; Laura Malerba; Angeliki Vakrinou; Mia Sherer; Ingo Helbig; Ala Somarowthu; Sanjay M Sisodiya; Roy Ben-Shalom; Renzo Guerrini; Nicola Specchio; Alfred L George Jr; Ethan M Goldberg

doi:10.1111/epi.18234

Rare dysfunctional SCN2A variants are associated with malformation of cortical development

Epilepsia. 2024 Dec 21. doi: 10.1111/epi.18234. Online ahead of print.

Authors

Jérôme Clatot^{1

2}, Christopher H Thompson³, Susan Sotardi⁴, Jinan Jiang⁵, Marina Trivisano⁶, Simona Balestrini^{7

8}, D Isum Ward⁹, Natalie Ginn^{1

2}, Brunetta Guaragni¹⁰, Laura Malerba¹¹, Angeliki Vakrinou¹², Mia Sherer¹³, Ingo Helbig^{1

2

14

15}, Ala Somarowthu¹, Sanjay M Sisodiya¹², Roy Ben-Shalom¹⁶, Renzo Guerrini^{7

8}, Nicola Specchio⁶, Alfred L George Jr³, Ethan M Goldberg^{1

2

15

16}

Affiliations

¹ Division of Neurology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
² The Epilepsy Neurogenetics Initiative, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
³ Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
⁴ Department of Radiology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁵ The University of California, Berkeley, California, USA.
⁶ Child Neurology, Epilepsy and Movement Disorders, Bambino Gesù, IRCCS Children's Hospital, Rome, Italy.
⁷ Department of Neuroscience and Medical Genetics, Meyer Children's Hospital IRCCS, Florence, Italy.
⁸ University of Florence, Florence, Italy.
⁹ Department of Pediatrics, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota, USA.
¹⁰ Neonatology and Neonatal Intensive Care Unit, Children's Hospital, ASST-Spedali Civili of Brescia, Brescia, Italy.
¹¹ Unit of Child Neurology and Psychiatry, ASST-Spedali Civili of Brescia, Brescia, Italy.
¹² Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.
¹³ Department of Neurology, The University of California, Sacramento, California, USA.
¹⁴ Department of Neurology, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹⁵ Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Pennsylvania, USA.
¹⁶ Department of Neuroscience, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

PMID: 39707911
DOI: 10.1111/epi.18234

Abstract

Objective: SCN2A encodes the voltage-gated sodium (Na+) channel α subunit Na_V1.2, which is important for the generation and forward and back propagation of action potentials in neurons. Genetic variants in SCN2A are associated with a spectrum of neurodevelopmental disorders. However, the mechanisms whereby variation in SCN2A leads to disease remains incompletely understood, and the full spectrum of SCN2A-related disorders may not be fully delineated.

Methods: Here, we identified seven de novo heterozygous variants in SCN2A in eight individuals with developmental and epileptic encephalopathy (DEE) accompanied by prominent malformation of cortical development (MCD). We characterized the electrophysiological properties of Na + currents in human embryonic kidney (HEK) cells transfected with the adult (A) or neonatal (N) isoform of wild-type (WT) and variant Na_V1.2 using manual and automated whole-cell voltage clamp recording.

Results: The neonatal isoforms of all SCN2A variants studied exhibit gain of function (GoF) with a large depolarized shift in steady-state inactivation, creating a markedly enhanced window current common across all four variants tested. Computational modeling demonstrated that expression of the Na_V1.2-p.Met1770Leu-N variant in a developing neocortical pyramidal neuron results in hyperexcitability.

Significance: These results support expansion of the clinical spectrum of SCN2A-related disorders and the association of genetic variation in SCN2A with MCD, which suggests previously undescribed roles for SCN2A in fetal brain development.

Keywords: SCN2A; Nav1.2; developmental and epileptic encephalopathy; malformation of cortical development; voltage‐gated sodium channel.

Abstract

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