Family-Based Whole-Exome Sequencing for Identifying Novel Variants in Consanguineous Families with Schizophrenia

Background Schizophrenia (SCZ) is a complex neuropsychiatric disorder characterized by pronounced genetic heterogeneity. Much of the genetic architecture of the disorder has not yet been clearly elucidated. Objectives In the present experimental genetic analysis study, we used the whole-exome sequencing (WES) approach to identify the SCZ-related genetic variants in consanguineous multi-affected families. Patients and Methods The current study was conducted between 2013 and 2015. The patients were recruited from two mental hospitals, including Razi hospital (Tehran, Iran) and Mirza Koochak Khan hospital (Rasht, Iran). All patients were diagnosed based on the DSM-IV-TR diagnostic criteria for SCZ. DNA samples from one proband for each of the three consanguineous Iranian families with twelve affected patients were subjected to WES. Then, a multi-step analysis strategy was employed to identify the genetic variants that may have potentially contributed to SCZ. Results After variant filtering, WES data revealed two previously known pathogenic mutations (rs450046 in PRODH and rs1800497 in ANKK1 genes) and five novel variants in five genes (NOS1, ANKK1, ARVCF, GRID1, and ANK3), all of which were predicted to be causing damage by SIFT, Polyphen-2, and MutationTaster tools. Two of these novel variants (c.562C > T in ANKK1 and c.7649G > T in ANK3) showed complete segregation in the families, which makes them good candidates for further case-control studies. Conclusions By applying WES, both novel and known SCZ pathogenic variants with complete or incomplete segregation in the families with multiple cases of schizophrenic patients were identified.