W87. rare, pathogenic copy number variants co-segregate with schizophrenia in pedigree cohort

Schizophrenia is a highly heritable mental disorder which results in significant co-morbidities and has a lifetime prevalence of ∼1%. Previous work has identified 12 rare copy number variants (CNVs) that increase individual risk for schizophrenia. However, large case-control cohorts are typically required to discover and characterize such variants. Family-based studies offer a unique alternative to evaluate rare variants, since multiplex pedigrees are more likely to be influenced by the same collection of variants than in an unrelated cohort. Additionally, the use of whole genome sequencing (WGS) technologies allows for a higher resolution and improved detection of CNVs compared to previous methods. We examined WGS data from 35 samples across six pedigrees from Utah multiply affected with schizophrenia. We applied a novel consensus CNV calling pipeline using four calling tools that incorporates relatedness information to support lower-confidence calls. We annotated CNVs if they had a full co-segregation pattern (carried by all affected samples in-family and absent from both unaffected and marry-in samples) or a reduced co-segregation pattern (carried by all but one affected sample in-family and absent from both unaffected and marry-in samples). Allele frequencies from gnomAD were annotated using SVAFotate, and the pathogenicity following the American College for Medical Genetics guidelines was evaluated using AnnotSV. We prioritized family-private CNVs with a full or reduced co-segregation pattern that were rare in gnomAD (allele frequency < 1%) and predicted to be pathogenic or likely pathogenic. This resulted in five deletions, two with a full co-segregation pattern and three with a reduced co-segregation pattern. Two of these deletions were removed following manual validation from the sequencing reads. One retained CNV was a 3.2kb deletion overlapping an intron-exon junction of PITRM1 that perfectly co-segregated with schizophrenia in one pedigree. The two remaining deletions had a reduced co-segregation pattern in their respective pedigrees, and as such show less evidence for association with schizophrenia. PITRM1 encodes for an ATP-dependent metalloprotease that is known to degrade post-cleavage mitochondrial transit peptides. It is known to be expressed across human brain tissue types and previously research has suggested a role in Alzheimer's disease and neurodegeneration. In the ClinVar database, pathogenic missense variants in PITRM1 have been reported for autosomal recessive spinocerebellar ataxia. In two recent family-based studies, carriers of these pathogenic missense variants have also had symptoms of both psychosis and intellectual disability. While PITRM1 has not been implicated in schizophrenia from rare or common variant studies, this presentation is consistent with the pleiotropy exhibited by schizophrenia associated CNVs for other psychiatric and neurological conditions.