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Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations.

  • Monteiro, Fabiola P1
  • Curry, Cynthia J2
  • Hevner, Robert3
  • Elliott, Stephen4
  • Fisher, Jamie H5
  • Turocy, John5
  • Dobyns, William B6
  • Costa, Larissa A1
  • Freitas, Erika1
  • Kitajima, João Paulo1
  • Kok, Fernando7
  • 1 Mendelics Genomic Analysis, CEP 04013-000, São Paulo, SP, Brazil. , (Brazil)
  • 2 Genetic Medicine, Department of Pediatrics, University of California, San Francisco/Fresno, CA, USA.
  • 3 Neuropathology, Department of Pathology, University of California, San Diego, CA, USA.
  • 4 Neonatology, Community Regional Medical Center, Fresno, California, USA.
  • 5 Genetics and Perinatology, Kaiser Permanente, Clovis, CA, USA.
  • 6 Center for Center for Integrative Brain Research Seattle Children's Research Institute, University of Washington, Seattle, WA, USA.
  • 7 Mendelics Genomic Analysis, CEP 04013-000, São Paulo, SP, Brazil; Neurogenetics, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, SP, Brazil. Electronic address: [email protected] , (Brazil)
Published Article
European journal of medical genetics
Publication Date
Jan 01, 2020
DOI: 10.1016/j.ejmg.2019.01.014
PMID: 30690204


The Na+/K+- ATPase acts as an ion pump maintaining the essential plasma membrane potential in all mammalian cell types, and is essential for many cellular functions. There are four α isoforms (α1, α2, α3 and α4) with distinct expression patterns, kinetic properties and substrate affinity. The α2-isoform is encoded by ATP1A2 and evidence supports its utmost importance in Cl- homeostasis in neurons, and in the function of respiratory neurons at birth. Monallelic pathogenic variants in ATP1A2 are associated with familial hemiplegic migraine type 2 (FHM2) and on rare occasions with alternating hemiplegia of childhood 1 (AHC1). To date, no instances of biallelic loss of function variants have been reported in humans. However, Atp1a2 homozygous loss of function knockout mice (α2-/- mice) show severe motor deficits, with lack of spontaneous movements, and are perinatally lethal due to absent respiratory activity. In this report we describe three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures (e.g. arthrogryposis), microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic loss of function variants in ATP1A2, predicted to be pathogenic were found on whole exome sequencing. We propose that this is a distinctive new syndrome caused by complete absence of Na+/K+- ATPase α2-isoform expression. Copyright © 2019. Published by Elsevier Masson SAS.

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