SETD1A variant-associated psychosis: A systematic review of the clinical literature and description of two new cases

Mark A Colijn; Prescilla Carrion; Guillaume Poirier-Morency; Sanja Rogic; Ivan Torres; Mahesh Menon; Michelle Lisonek; Courtney Cook; Ashley DeGraaf; Subramanya Ponnachana Thammaiah; Harish Neelakant; Veerle Willaeys; Olga Leonova; Randall F White; Stephen Yip; Andrew J Mungall; Patrick M MacLeod; William T Gibson; Patrick F Sullivan; William G Honer; Paul Pavlidis; Robert M Stowe

doi:10.1016/j.pnpbp.2023.110888

SETD1A variant-associated psychosis: A systematic review of the clinical literature and description of two new cases

Prog Neuropsychopharmacol Biol Psychiatry. 2024 Feb 8:129:110888. doi: 10.1016/j.pnpbp.2023.110888. Epub 2023 Oct 31.

Authors

Mark A Colijn¹, Prescilla Carrion², Guillaume Poirier-Morency³, Sanja Rogic⁴, Ivan Torres⁵, Mahesh Menon², Michelle Lisonek⁶, Courtney Cook⁷, Ashley DeGraaf⁸, Subramanya Ponnachana Thammaiah⁹, Harish Neelakant², Veerle Willaeys¹⁰, Olga Leonova², Randall F White², Stephen Yip¹¹, Andrew J Mungall¹², Patrick M MacLeod⁷, William T Gibson¹³, Patrick F Sullivan¹⁴, William G Honer¹⁵, Paul Pavlidis¹⁶, Robert M Stowe¹⁷

Affiliations

¹ Department of Psychiatry, Hotchkiss Brain Institute, and Mathison Centre for Mental Health Research & Education, University of Calgary, Calgary, AB, Canada. Electronic address: mark.colijn2@ucalgary.ca.
² Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
³ Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.
⁴ Department of Psychiatry and Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.
⁵ Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada; BC Mental Health and Substance Use Services, Vancouver, BC, Canada.
⁶ University of British Columbia, Vancouver, BC, Canada.
⁷ Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
⁸ Heart Centre, St. Paul's Hospital and Providence Health, Vancouver, BC, Canada.
⁹ Langley Mental Health and Substance Use Services, Fraser Health Authority, Langley, BC, Canada.
¹⁰ BC Psychosis Program, British Columbia Mental Health & Substance Use Services, Vancouver, BC, Canada.
¹¹ Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
¹² Canada's Michael Smith Genome Sciences Centre, Vancouver, BC, Canada.
¹³ Department of Medical Genetics, University of British Columbia and BC Children's Hospital Research Institute, Vancouver, BC, Canada.
¹⁴ Psychiatry and Genetics, University of North Carolina at Chapel Hill, NC, USA; Karolinska Institut, Stockholm, Sweden.
¹⁵ Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada; BC Mental Health and Substance Use Services Research Institute, Vancouver, BC, Canada.
¹⁶ Department of Psychiatry, Michael Smith Laboratories, and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.
¹⁷ Departments of Psychiatry and Neurology (Medicine), BC Neuropsychiatry Program, and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.

PMID: 37918557
DOI: 10.1016/j.pnpbp.2023.110888

Abstract

Objective: SETD1A encodes a histone methyltransferase involved in various cell cycle regulatory processes. Loss-of-function SETD1A variants have been associated with numerous neurodevelopmental phenotypes, including intellectual disability and schizophrenia. While the association between rare coding variants in SETD1A and schizophrenia has achieved genome-wide significance by rare variant burden testing, only a few studies have described the psychiatric phenomenology of such individuals in detail. This systematic review and case report aims to characterize the neurodevelopmental and psychiatric phenotypes of SETD1A variant-associated schizophrenia.

Methods: A PubMed search was completed in July 2022 and updated in May 2023. Only studies that reported individuals with a SETD1A variant as well as a primary psychotic disorder were ultimately included. Additionally, another two previously unpublished cases of SETD1A variant-associated psychosis from our own sequencing cohort are described.

Results: The search yielded 32 articles. While 15 articles met inclusion criteria, only five provided case descriptions. In total, phenotypic information was available for 11 individuals, in addition to our own two unpublished cases. Our findings suggest that although individuals with SETD1A variant-associated schizophrenia may share a number of common features, phenotypic variability nonetheless exists. Moreover, although such individuals may exhibit numerous other neurodevelopmental features suggestive of the syndrome, their psychiatric presentations appear to be similar to those of general schizophrenia populations.

Conclusions: Loss-of-function SETD1A variants may underlie the development of psychosis in a small percentage of individuals with schizophrenia. Identifying such individuals may become increasingly important, given the potential for advances in precision medicine treatment approaches.

Keywords: Psychiatric genetics; Psychosis; SETD1A; Schizophrenia.

Publication types

Systematic Review
Case Reports
Review

MeSH terms

Genetic Predisposition to Disease
Humans
Intellectual Disability* / genetics
Phenotype
Psychotic Disorders* / genetics
Psychotic Disorders* / psychology
Schizophrenia* / genetics

Substances

Setd1A protein, human