Identification of putative second genetic hits in schizophrenia carriers of high-risk copy number variants and resequencing in additional samples

Eur Arch Psychiatry Clin Neurosci. 2018 Sep;268(6):585-592. doi: 10.1007/s00406-017-0799-5. Epub 2017 Apr 18.


Copy number variants (CNVs) conferring risk of schizophrenia present incomplete penetrance, suggesting the existence of second genetic hits. Identification of second hits may help to find genes with rare variants of susceptibility to schizophrenia. The aim of this work was to search for second hits of moderate/high risk in schizophrenia carriers of risk CNVs and resequencing of the relevant genes in additional samples. To this end, ten patients with risk CNVs at cytobands 15q11.2, 15q11.2-13.1, 16p11.2, or 16p13.11, were subjected to whole-exome sequencing. Rare single nucleotide variants, defined as those absent from main public databases, were classified according to bioinformatic prediction of pathogenicity by CADD scores. The average number of rare predicted pathogenic variants per sample was 13.6 (SD 2.01). Two genes, BFAR and SYNJ1, presented rare predicted pathogenic variants in more than one sample. Follow-up resequencing of these genes in 432 additional cases and 432 controls identified a significant excess of rare predicted pathogenic variants in case samples at SYNJ1. Taking into account its function in clathrin-mediated synaptic vesicle endocytosis at presynaptic terminals, our results suggest an impairment of this process in schizophrenia.

Keywords: DNA copy number variations; Exome; High-throughput nucleotide sequencing; Psychosis; Rare variant.

MeSH terms

  • DNA Copy Number Variations / genetics*
  • Genetic Predisposition to Disease
  • Heterozygote*
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Phosphoric Monoester Hydrolases / genetics*
  • Risk
  • Schizophrenia / genetics*
  • Whole Exome Sequencing / methods*


  • Phosphoric Monoester Hydrolases
  • phosphoinositide 5-phosphatase