RGS3andIL1RAPL1missense variants implicate defective neurotransmission in early-onset inherited schizophrenias

Abstract

Psychosis affects 3% of the world's population. 1 The most common diagnosis associated with psychosis is schizophrenia, with a worldwide prevalence of 1%. Schizophrenia is a chronic, frequently disabling, lifelong illness. Patients may experience hallucinations, delusions, paranoia, catatonia, disorganized thinking, functional impairment, poor planning, flattening behaviour and social withdrawal.Schizophrenia has a strong genetic component, with about 80% to 85% heritability as estimated through family, twin and adoption studies. 2 In the past 2 decades, worldwide collaborations have enabled genome-wide association studies with large cohorts, in search of genetic risk loci associated with schizophrenia. More than 176 loci have been associated with schizophrenia through case-control association studies of 56 000 patients with schizophrenia and 78 000 controls. 3 Many copy-number variants have also been implicated as causes of schizophrenia. 4 Although schizophrenia is considered to be a complex disorder with common variants of multiple genes involved in causing the phenotype, rare high-impact variants also contribute to the disorder. In a large cohort study, whole-genome sequencing was performed in 112 patients affected with extreme early-onset, treatment-resistant schizophrenia and whole-exome sequencing was completed for 4185 controls. 5 The research revealed several rare, damaging missense variants in multiple genes, of which ACACA:p.(Asp251Gly), CACNA1C:p.(Ile1153Arg) and GABRA:p.(Thr234Ala) had been previously associated with schizophrenia. A total of 48.2% of patients with treatmentresistant schizophrenia had at least 1 damaging missense or loss-of-function variant in a variant-intolerant gene, compared to 25.4% in controls. Interestingly, loss-of-function variants in genes were significantly enhanced for Mendelian syndromes in which some patients also exhibit aggressive behaviours or hallucinations. Moreover, many genes previously associated with schizophrenia had higher numbers of both missense and lossof-function variants compared to controls. 5

Genome Sequencing of Consanguineous Family Implicates Ubiquitin-Specific Protease 53 (USP53) Variant in Psychosis/Schizophrenia: Wild-Type Expression in Murine Hippocampal CA 1–3 and Granular Dentate with AMPA Synapse Interactions

“…Whole-exome sequencing, variant filtering, and analyses were performed for the two patients and their father as described previously [18], and the exome data were mapped…”

“…Whole-exome sequencing, variant filtering, and analyses were performed for the two patients and their father as described previously [18], and the exome data were mapped to GRCh37/hg19 genome assembly. Variants were prioritized based on the following filters: (1) rarity (MAF < 0.01).…”

“…The identification of disease-associated, rare, Mendelian recessive variants based on the approach used here is well-established in medical genetics [65,66]. However, this approach has seen limited application in finding Mendelian genes for common mental illness [3,17,18]. Given the MAF and consanguinity suggesting a rare genetic form of schizophrenia, the variant will not be a common cause despite the common phenotype.…”

CRISPR/Cas9-mediated knockout of IL1RAPL1 in stem cells highlights a role in neural cell migration during cortical development

“…This is a transmembrane protein belonging to the Toll/IL-1 receptor family. Rare genetic variants in IL1RAPL1 gene have been reported in individuals with ID 4 , autism 5 and schizophrenia 6,7 . Most of the described mutations are deletions of exons 1-6, which codes for the extracellular domain of the IL1RAPL1 protein.…”