Missense variants in ATP1A3 and FXYD gene family are associated with childhood-onset schizophrenia

Boris Chaumette, Vladimir Ferrafiat, Amirthagowri Ambalavanan, Alice Goldenberg, Alexandre Dionne-Laporte, Dan Spiegelman, Patrick A. Dion, Priscille Gerardin, Claudine Laurent, David Cohen, Judith Rapoport, Guy A. Rouleau

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia defined as onset before age of 13. Here we report on two unrelated cases diagnosed with both COS and alternating hemiplegia of childhood (AHC), and for whom two distinct pathogenic de novo variants were identified in the ATP1A3 gene. ATP1A3 encodes the α-subunit of a neuron-specific ATP-dependent transmembrane sodium–potassium pump. Using whole exome sequencing data derived from a cohort of 17 unrelated COS cases, we also examined ATP1A3 and all of its interactors known to be expressed in the brain to establish if variants could be identified. This led to the identification of a third case with a possibly damaging missense mutation in ATP1A3 and three others cases with predicted pathogenic missense variants in the FXYD gene family (FXYD1, FXYD6, and FXYD6-FXYD2 readthrough). FXYD genes encode proteins that modulate the ATP-dependant pump function. This report is the first to identify variants in the same pathway for COS. Our COS study illustrates the interest of stratifying a complex condition according to the age of onset for the identification of deleterious variants. Whereas ATP1A3 is a replicated gene in rare neuropediatric diseases, this gene has previously been linked with COS in only one case report. The association with rare variants in FXYD gene family is novel and highlights the interest of exploring these genes in COS as well as in pediatric neurodevelopmental disorders.

Original languageEnglish
Pages (from-to)821-830
Number of pages10
JournalMolecular Psychiatry
Issue number4
StatePublished - 1 Apr 2020
Externally publishedYes


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