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

Abstract

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 (WES) 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.

Childhood-Onset Schizophrenia: A Systematic Overview of Its Genetic Heterogeneity From Classical Studies to the Genomic Era

“…In total, 32 candidate genes have been described on 12 autosomes (1, 2, 3, 6, 7, 8, 11, 13, 15, 17, 19, and 22) and 1 sex chromosome (X) (Tables 1 and 2) through the following studies (Addington et al, 2004;Sekizawa et al, 2004;Gornick et al, 2005;Addington et al, 2005;Addington et al, 2007;Pakhomova et al, 2010;Addington et al, 2011;Raznahan et al, 2011;Smedemark-Margulies et al, 2016;Chaumette et al, 2018;Ambalavanan et al, 2019):…”

“…Finally, five studies by DNA sequencing (candidate genes or whole exome sequencing) have allowed identifying the following 18 mutations in 11 genes (Addington et al, 2011;Ambalavanan et al, 2016;Smedemark-Margulies et al, 2016;Chaumette et al, 2018;Ambalavanan et al, 2019). i.…”

The Implementation, Diagnostic Yield and Clinical Outcome of Genetic Testing on an Inpatient Child and Adolescent Psychiatry Service

“…ID, ASD, GDD) to include COS, complex psychiatric presentation and a family history enriched for psychiatric disorders. COS is a rare and severe NDD with a reported enrichment of known NDD-associated pathogenic CNVs compared to both matched, related controls and patients with adult-onset schizophrenia 23 , as well as disease-associated SNVs [24][25][26] . We were careful to include only those patients who had a well-documented history of psychosis-onset prior to the beginning of puberty.…”

Exploratory Analysis of Rare and Novel Variants in Mexican Patients Diagnosed with Schizophrenia and Dementia

“…The overall effect of these variants on the etiology of neuropsychiatric disorders is still under study, although some hypotheses have been proposed. For instance, a recent WES and WGS analysis of neuropsychiatric patients has proposed that an increase of damaging variants on these genes could decrease the age of Alzheimer's onset 109 , and that the age of onset of SCZ and autism-spectrum disorders could be influenced by the accumulation of de novo variants in genes involved in neurodevelopmental processes 110,111 .…”