RCL1 copy number variants are associated with a range of neuropsychiatric phenotypes

Mendelian and early-onset severe psychiatric phenotypes often involve genetic variants having a large effect, offering opportunities for genetic discoveries and early therapeutic interventions. Here, the index case is an 18-year-old boy, who at 14 years of age had a decline in cognitive functioning...

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Published in:	Molecular psychiatry Vol. 26; no. 5; pp. 1706 - 1718
Main Authors:	Brownstein, Catherine A., Smith, Richard S., Rodan, Lance H., Gorman, Mark P., Hojlo, Margaret A., Garvey, Emily A., Li, Jianqiao, Cabral, Kristin, Bowen, Joshua J., Rao, Abhijit S., Genetti, Casie A., Carroll, Devon, Deaso, Emma A., Agrawal, Pankaj B., Rosenfeld, Jill A., Bi, Weimin, Howe, Jennifer, Stavropoulos, Dimitri J., Hansen, Adam W., Hamoda, Hesham M., Pinard, Ferne, Caracansi, Annmarie, Walsh, Christopher A., D’Angelo, Eugene J., Beggs, Alan H., Zarrei, Mehdi, Gibbs, Richard A., Scherer, Stephen W., Glahn, David C., Gonzalez-Heydrich, Joseph
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-05-2021 Nature Publishing Group
Subjects:	45/23 45/61 631/208 692/699/476 Age Behavioral Sciences Biological Psychology Brain research Case studies Catatonia Cognitive ability Copy number Copy number variations Dosage Families & family life Genes Genetic aspects Genetic diversity Genetics Genomes Genomics Genotype & phenotype Hallucinations Hospitals Medicine Medicine & Public Health Mental disorders Mental illness Mood Mutation Neurologic manifestations of general diseases Neurosciences Pharmacotherapy Phenotype Phenotypes Psychiatry Schizophrenia Sensory integration Therapeutic applications United States
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Summary:	Mendelian and early-onset severe psychiatric phenotypes often involve genetic variants having a large effect, offering opportunities for genetic discoveries and early therapeutic interventions. Here, the index case is an 18-year-old boy, who at 14 years of age had a decline in cognitive functioning over the course of a year and subsequently presented with catatonia, auditory and visual hallucinations, paranoia, aggression, mood dysregulation, and disorganized thoughts. Exome sequencing revealed a stop-gain mutation in RCL1 (NM_005772.4:c.370 C > T, p.Gln124Ter), encoding an RNA 3′-terminal phosphate cyclase-like protein that is highly conserved across eukaryotic species. Subsequent investigations across two academic medical centers identified eleven additional cases of RCL1 copy number variations (CNVs) with varying neurodevelopmental or psychiatric phenotypes. These findings suggest that dosage variation of RCL1 contributes to a range of neurological and clinical phenotypes.
Bibliography:	ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3
ISSN:	1359-4184 1476-5578
DOI:	10.1038/s41380-021-01035-y