Exome sequencing of ATP1A3-negative cases of alternating hemiplegia of childhood reveals SCN2A as a novel causative gene.

Anne-Lise Poulat, Erin L Heinzen, Arn M J M van den Maagdenberg, Fiorella Gurrieri, Alfred L George, Christopher H Thompson, Jan Koenderink, Rosaria Vavassori, Alexis Arzimanoglou, Marie-Cecile Nassogne, Anne Lépine, Vincent Des Portes, Eleni Panagiotakaki, Elisa De Grandis, Nicole M Walley, Aster V E Harder, Lorena Di Pietro, Agnese Novelli, Emanuela Abiusi, Gaetan Lesca, Sophie Nicole, Lisanne S Vijfhuizen, Mohamad A Mikati, Francesco D Tiziano

Journal: European journal of human genetics : EJHG 2024;32(2):224-231

PMID: 38097767

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Abstract

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopment disorder that is typically characterized by debilitating episodic attacks of hemiplegia, seizures, and intellectual disability. Over 85% of individuals with AHC have a de novo missense variant in ATP1A3 encoding the catalytic α3 subunit of neuronal NaK ATPases. The remainder of the patients are genetically unexplained. Here, we used next-generation sequencing to search for the genetic cause of 26 ATP1A3-negative index patients with a clinical presentation of AHC or an AHC-like phenotype. Three patients had affected siblings. Using targeted sequencing of exonic, intronic, and flanking regions of ATP1A3 in 22 of the 26 index patients, we found no ultra-rare variants. Using exome sequencing, we identified the likely genetic diagnosis in 9 probands (35%) in five genes, including RHOBTB2 (n = 3), ATP1A2 (n = 3), ANK3 (n = 1), SCN2A (n = 1), and CHD2 (n = 1). In follow-up investigations, two additional ATP1A3-negative individuals were found to have rare missense SCN2A variants, including one de novo likely pathogenic variant and one likely pathogenic variant for which inheritance could not be determined. Functional evaluation of the variants identified in SCN2A and ATP1A2 supports the pathogenicity of the identified variants. Our data show that genetic variants in various neurodevelopmental genes, including SCN2A, lead to AHC or AHC-like presentation. Still, the majority of ATP1A3-negative AHC or AHC-like patients remain unexplained, suggesting that other mutational mechanisms may account for the phenotype or that cases may be explained by oligo- or polygenic risk factors.

Address: Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, Member of the ERN EpiCare, University Hospitals of Lyon (HCL), Lyon, France.; Institute of Genomic Medicine, Catholic University and Policlinico Gemelli, Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Rome, Italy.; Division of Pediatric Neurology and Developmental Medicine, Duke University, Durham, NC, USA.; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.; Institute of Functional Genomics, University of Montpellier, CNRS, INSERM, Montpellier, France.; Department of Medical Genetics, University Hospital of Lyon and Claude Bernard Lyon I University, Lyon France - Pathophysiology and Genetics of Neuron and Muscle (PNMG), UCBL, CNRS UMR5261 - INSERM U1315, Lyon, France.; Department of Life Sciences and Public Health, Section of Genomic Medicine, Università Cattolica del Sacro Cuore, Roma, Italy.; Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.; Department of Pediatrics, Division of Medical Genetics, Duke Health, Durham, NC, USA.; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.; Child Neuropsychiatry Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy.; Pediatric Neurology Department, Member of the ERN EpiCARE, University Hospitals of Lyon (HCL), Lyon, France.; Service de neuropédiatrie, Centre hospitalo universitaire de la Timone, Marseille, France.; Institut des Maladies Rares, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium.; Service de Neurologie Pédiatrique, Member of the ERN MetabERN, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium.; Department of Child Neurology and Epilepsy Research Unit, Member of the ERN EpiCARE, Hospital San Juan de Dios, Barcelona, Spain.; Euro-Mediterranean Institute for Science and Technology I.E.ME.S.T., Palermo, Italy.; Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Department of Medicine, Research Unit of Medical Genetics, Università Campus Bio-Medico di Roma, Roma, Italy.; Operative Research Unit of Medical Genetics Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy.; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. [email protected].; Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. [email protected].; Division of Pharmacology and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].; Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].

DOI: 10.1038/s41431-023-01489-4

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MeSH Terms: Humans, Hemiplegia, Exome Sequencing, Mutation, Mutation, Missense, Sodium-Potassium-Exchanging ATPase, GTP-Binding Proteins, Tumor Suppressor Proteins, NAV1.2 Voltage-Gated Sodium Channel