ATP2B2 de novo variants as a cause of variable neurodevelopmental disorders that feature dystonia, ataxia, intellectual disability, behavioral symptoms, and seizures.

ATP2B2 encodes the variant-constrained plasma-membrane calcium-transporting ATPase-2, expressed in sensory ear cells and specialized neurons. ATP2B2/Atp2b2 variants were previously linked to isolated hearing loss in patients and neurodevelopmental deficits with ataxia in mice. We aimed to establish the association between ATP2B2 and human neurological disorders. Multinational case recruitment, scrutiny of trio-based genomics data, in silico analyses, and functional variant characterization were performed. We assembled 7 individuals harboring rare, predicted deleterious heterozygous ATP2B2 variants. The alleles comprised 5 missense substitutions that affected evolutionarily conserved sites and 2 frameshift variants in the penultimate exon. For 6 variants, a de novo status was confirmed. Unlike described patients with hearing loss, the individuals displayed a spectrum of neurological abnormalities, ranging from ataxia with dystonic features to complex neurodevelopmental manifestations with intellectual disability, autism, and seizures. Two cases with recurrent amino-acid variation showed distinctive overlap with cerebellar atrophy-associated ataxia and epilepsy. In cell-based studies, all variants caused significant alterations in cytosolic calcium handling with both loss- and gain-of-function effects. Presentations in our series recapitulate key phenotypic aspects of Atp2b2-mouse models and underline the importance of precise calcium regulation for neurodevelopment and cerebellar function. Our study documents a role for ATP2B2 variants in causing heterogeneous neurodevelopmental and movement-disorder syndromes. Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Citation

Elena Poggio, Lucia Barazzuol, Andrea Salmaso, Celeste Milani, Adamantia Deligiannopoulou, Ángeles García Cazorla, Se Song Jang, Natalia Juliá-Palacios, Boris Keren, Robert Kopajtich, Sally Ann Lynch, Cyril Mignot, Catherine Moorwood, Christiane Neuhofer, Vincenzo Nigro, Anna Oostra, Holger Prokisch, Virginie Saillour, Nika Schuermans, Annalaura Torella, Patrick Verloo, Elise Yazbeck, Marcella Zollino, Robert Jech, Juliane Winkelmann, Jan Necpal, Tito Calì, Marisa Brini, Michael Zech. ATP2B2 de novo variants as a cause of variable neurodevelopmental disorders that feature dystonia, ataxia, intellectual disability, behavioral symptoms, and seizures. Genetics in medicine : official journal of the American College of Medical Genetics. 2023 Dec;25(12):100971

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PMID: 37675773

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