Multiple rare inherited variants in a four generation schizophrenia family offer leads for complex mode of disease inheritance

Schizophrenia is a clinically and genetically heterogeneous neuropsychiatric disorder, with a polygenic basis but identification of the specific determinants is a continuing challenge. In this study, we analyzed a multigenerational family, with all healthy individuals in the first two generations, and four progeny affected with schizophrenia in the subsequent two generations, using whole exome sequencing. We identified five rare protein sequence altering heterozygous variants, in five different genes namely SMARCA5, PDE1B, TNIK, SMARCA2 and FLRT shared among all affected members and predicted to be damaging. Variants in SMARCA5 and PDE1B were inherited from the unaffected father whereas variants in TNIK, SMARCA2 and FLRT1 were inherited from the unaffected mother in all the three affected individuals in the third generation; and notably all these five variants were transmitted by an affected mother to her affected son. Microsatellite based analysis lent a modest linkage support (LOD score of 1.2; θ=0.0 at each variant). Of note, analysis of exome data of an ancestry matched unrelated schizophrenia cohort (n = 350), revealed a total of 16 rare variants (MAF 0.01) in these five genes. Interestingly, these five genes involved in neurodevelopmental and/or neurotransmitter signaling processes are implicated in the etiology of schizophrenia previously. This study provides good evidence for a likely cumulative contribution of multiple rare variants from disease relevant genes with a threshold effect in disease development and seems to explain the unusual disease transmission pattern generally witnessed in such conditions, but warrants extensive replication efforts in families with similar complex disease inheritance profiles.