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

Catherine A. Brownstein; Richard S. Smith; Lance H. Rodan; Mark P. Gorman; Margaret A. Hojlo; Emily A. Garvey; Jianqiao Li; Kristin Cabral; Joshua J. Bowen; Abhijit S. Rao; Casie A. Genetti; Devon Carroll; Emma A. Deaso; Pankaj B. Agrawal; Jill A. Rosenfeld; Weimin Bi; Jennifer Howe; Dimitri J. Stavropoulos; Adam W. Hansen; Hesham M. Hamoda; Ferne Pinard; Annmarie Caracansi; Christopher A. Walsh; Eugene J. D’Angelo; Alan H. Beggs; Mehdi Zarrei; Richard A. Gibbs; Stephen W. Scherer; David C. Glahn; Joseph Gonzalez-Heydrich

doi:10.1038/s41380-021-01035-y

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

Catherine A. Brownstein^*, Richard S. Smith, Lance H. Rodan, Mark P. Gorman, Margaret A. Hojlo, Emily A. Garvey, Jianqiao Li, Kristin Cabral, Joshua J. Bowen, Abhijit S. Rao, Casie A. Genetti, Devon Carroll, Emma A. Deaso, Pankaj B. Agrawal, Jill A. Rosenfeld, Weimin Bi, Jennifer Howe, Dimitri J. Stavropoulos, Adam W. Hansen, Hesham M. HamodaFerne Pinard, Annmarie Caracansi, Christopher A. Walsh, Eugene J. D’Angelo, Alan H. Beggs, Mehdi Zarrei, Richard A. Gibbs, Stephen W. Scherer, David C. Glahn, Joseph Gonzalez-Heydrich

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1706-1718
Number of pages	13
Journal	Molecular Psychiatry
Volume	26
Issue number	5
DOIs	https://doi.org/10.1038/s41380-021-01035-y
State	Published - May 2021

Funding

Acknowledgements The authors are grateful for the participation of the families reported herein and Johnathan Hecht for assistance with human tissue. Human tissue was obtained from the NIH NeuroBio-Bank at the University of Maryland, Baltimore, MD. We acknowledge the referring clinicians for providing clinical samples and data used in this analysis. Support was provided by Stanley Center of the Broad Institute, Tommy Fuss Center for Neuropsychiatric Disease Research, Anne and Paul Marcus Family Foundation, Robin and Jonathan Klein Family, and NIH U54 HD090255 in support of the Boston Children’s Hospital IDDRC Molecular Genetics Core Facility. Additional work was supported by NIH F32 NS100033801 and K99 NS112604 to RS and R01 NS035129 to CAW. The authors thank the Centre for Applied Genomics and the University of Toronto McLaughlin Centre for technical support and funding. SWS holds the GlaxoSmithKline-CIHR Chair in Genome Sciences at The Hospital for Sick Children and the University of Toronto.

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Molecular Biology

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Brownstein, C. A., Smith, R. S., Rodan, L. H., Gorman, M. P., Hojlo, M. A., Garvey, E. A., Li, J., Cabral, K., Bowen, J. J., Rao, A. S., Genetti, C. A., Carroll, D., Deaso, E. A., Agrawal, P. B., Rosenfeld, J. A., Bi, W., Howe, J., Stavropoulos, D. J., Hansen, A. W., ... Gonzalez-Heydrich, J. (2021). RCL1 copy number variants are associated with a range of neuropsychiatric phenotypes. Molecular Psychiatry, 26(5), 1706-1718. https://doi.org/10.1038/s41380-021-01035-y

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abstract = "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.",

author = "Brownstein, {Catherine A.} and Smith, {Richard S.} and Rodan, {Lance H.} and Gorman, {Mark P.} and Hojlo, {Margaret A.} and Garvey, {Emily A.} and Jianqiao Li and Kristin Cabral and Bowen, {Joshua J.} and Rao, {Abhijit S.} and Genetti, {Casie A.} and Devon Carroll and Deaso, {Emma A.} and Agrawal, {Pankaj B.} and Rosenfeld, {Jill A.} and Weimin Bi and Jennifer Howe and Stavropoulos, {Dimitri J.} and Hansen, {Adam W.} and Hamoda, {Hesham M.} and Ferne Pinard and Annmarie Caracansi and Walsh, {Christopher A.} and D{\textquoteright}Angelo, {Eugene J.} and Beggs, {Alan H.} and Mehdi Zarrei and Gibbs, {Richard A.} and Scherer, {Stephen W.} and Glahn, {David C.} and Joseph Gonzalez-Heydrich",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.",

year = "2021",

month = may,

doi = "10.1038/s41380-021-01035-y",

language = "English (US)",

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Brownstein, CA, Smith, RS, Rodan, LH, Gorman, MP, Hojlo, MA, Garvey, EA, Li, J, Cabral, K, Bowen, JJ, Rao, AS, Genetti, CA, Carroll, D, Deaso, EA, Agrawal, PB, Rosenfeld, JA, Bi, W, Howe, J, Stavropoulos, DJ, Hansen, AW, Hamoda, HM, Pinard, F, Caracansi, A, Walsh, CA, D’Angelo, EJ, Beggs, AH, Zarrei, M, Gibbs, RA, Scherer, SW, Glahn, DC & Gonzalez-Heydrich, J 2021, 'RCL1 copy number variants are associated with a range of neuropsychiatric phenotypes', Molecular Psychiatry, vol. 26, no. 5, pp. 1706-1718. https://doi.org/10.1038/s41380-021-01035-y

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

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