Objective: This study aimed to determine in a systematic manner if the C9orf72 phenotype might extend beyond frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) to include psychiatric disease. Methods: A validated semi-structured family history interview was conducted in a large cohort of patients with FTD and ALS (n=89), with and without the C9orf72 expansion (n=29 and n=60 respectively) encompassing 1,414 first and second-degree relatives. Statistical analyses employed both the hazard ratio (HR) and relative risk ratio (RR) to determine the risk profiles within families. Results: A significant hazard ratio (HR) of 4.9 (95% CI: 1.9 - 13.9, p=0.003), confirmed a higher probability of developing schizophrenia for relatives of C9orf72 carriers compared to non-carriers. In total eight relatives of C9orf72 carriers experienced an episode of late-onset psychosis unrelated to schizophrenia, in comparison to one non-carrier (HR=17.9, 95% CI: 2.2, 143.2, p=0.007). The probability of suicide was also significantly higher for family members of C9orf72 carriers (HR=2.7, 95% CI 1.2,6.2, p=0.02). A HR of 2.7 (95% CI: 1.1 - 6.9, p=0.03) indicated a higher probability for Autism Spectrum Disorder (ASD) in family members of C9orf72 carriers, and this risk extended to FTD. Furthermore, there was a positive association between psychosis in probands and mental health disorders including ASD in their family members (p=0.04). Conclusion: Overall the results from this study suggest that a psychiatric phenotype exists within C9orf72 kindreds, Further studies should attempt to delineate the risk for psychiatric disorders in C9orf72 kindreds, to aid in clinical decision-making particularly regarding genetic counseling, through collaborations between neurology and psychiatry.

Psychiatric disorders in C9orf72 carriers and non-carriers - age of onset and survivalSupplementary Table 1: Age of onset (in years) of psychiatric disorders in C9orf72 carrier and non-carrier kindreds. Cox regression analysis hazard ratio (HR) with 95% confidence intervals (CI) shows effect of genetic status on survival in family members with psychiatric disorders.Supplementary table 1.docxRisk for psychiatric disorders in C9orf72 FTD and ALS kindredsRates (first 2 columns) of psychiatric disorders in C9orf72 FTD and ALS kindreds, and risk for psychiatric disorders between kindreds of probands with C9orf72 FTD vs ALS. Hazard ratios (HR) represent the risk to relatives of developing psychiatric disorders with upper and lower confidence intervals (CI) displayed. Significant values are highlighted in bold.Supplementary Table 2.docx