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Several large-scale whole-exome sequencing studies in patients with schizophrenia (SCZ) and autism spectrum disorder (ASD) have identified rare variants with modest or strong effect size as genetic risk factors. Dysregulation of cellular calcium homeostasis might be involved in SCZ/ASD pathogenesis, and genes encoding L-type voltage-gated calcium channel (VGCC) subunits Ca v 1.1 ( CACNA1S ), Ca v 1.2 ( CACNA1C ), Ca v 1.3 ( CACNA1D ), and T-type VGCC subunit Ca v 3.3 ( CACNA1I ) recently were identified as risk loci for psychiatric disorders. We performed a screening study, using the Ion Torrent Personal Genome Machine (PGM), of exon regions of these four candidate genes ( CACNA1C, CACNA1D, CACNA1S, CACNA1I ) in 370 Japanese patients with SCZ and 192 with ASD. Variant filtering was applied to identify biologically relevant mutations that were not registered in the dbSNP database or that have a minor allele frequency of less than 1% in East-Asian samples from databases; and are potentially disruptive, including nonsense, frameshift, canonical splicing site single nucleotide variants (SNVs), and non-synonymous SNVs predicted as damaging by five different  in silico  analyses. Each of these filtered mutations were confirmed by Sanger sequencing. If parental samples were available, segregation analysis was employed for measuring the inheritance pattern. Using our filter, we discovered one nonsense SNV (p.C1451* in  CACNA1D ), one  de novo  SNV (p.A36V in  CACNA1C ), one rare short deletion (p.E1675del in  CACNA1D ), and 14 NSstrict SNVs (non-synonymous SNV predicted as damaging by all of five  in silico  analyses). Neither p.A36V in  CACNA1C  nor p.C1451* in  CACNA1D  were found in 1871 SCZ cases, 380 ASD cases, or 1916 healthy controls in the independent sample set, suggesting that these SNVs might be ultra-rare SNVs in the Japanese population. The neuronal splicing isoform of Ca v 1.2 with the p.A36V mutation, discovered in the present study, showed reduced Ca 2+ -dependent inhibition, resulting in excessive Ca 2+  entry through the mutant channel. These results suggested that this  de novo  SNV in  CACNA1C  might predispose to SCZ by affecting Ca 2+  homeostasis. Thus, our analysis successfully identified several ultra-rare and potentially disruptive gene variants, lending partial support to the hypothesis that VGCC-encoding genes may contribute to the risk of SCZ/ASD.

translational psychiatry

Identification of ultra-rare disruptive variants in voltage-gated calcium channel-encoding genes in Japanese samples of schizophrenia and autism spectrum disorder