The aim of this study was 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 semistructured 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 used both the hazard ratio (HR) and the relative risk ratio to determine the risk profiles within families.Results
A significant HR of 4.9 (95% confidence interval [CI]: 1.9–13.9, p = 0.003) confirmed a higher probability of developing schizophrenia for relatives of C9orf72 carriers compared with noncarriers. In addition, 8 relatives of C9orf72 carriers experienced an episode of late-onset psychosis unrelated to schizophrenia, in comparison to one noncarrier (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). An HR of 2.7 (95% CI: 1.1–6.9, p = 0.03) indicated a higher probability of 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 of psychiatric disorders in C9orf72 kindreds to aid in clinical decision making, particularly regarding genetic counseling, through collaborations between neurology and psychiatry.