University of Oulu

Rahikkala, E., Urpa, L., Ghimire, B. et al. A novel variant in SMG9 causes intellectual disability, confirming a role for nonsense-mediated decay components in neurocognitive development. Eur J Hum Genet 30, 619–627 (2022). https://doi.org/10.1038/s41431-022-01046-5

A novel variant in SMG9 causes intellectual disability, confirming a role for nonsense-mediated decay components in neurocognitive development

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Author: Rahikkala, Elisa1,2; Urpa, Lea3; Ghimire, Bishwa3;
Organizations: 1Department of Clinical Genetics, PEDEGO Research Unit and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
2Institute of Biomedicine, University of Turku, Turku, Finland
3Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
4Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
5Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
6The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
7Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
8Cancer and Translational Medicine Research Unit and Biocenter Oulu, University of Oulu, NordLab Oulu, Oulu, Finland
9Center for Intellectual Disability Care, Oulu University Hospital, Oulu, Finland
10Centogene GmbH, 18055, Rostock, Germany
11Medical Faculty, University of Rostock, Rostock, Germany
12Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
13Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
14Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USAAnalytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.9 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022102162733
Language: English
Published: Springer Nature, 2022
Publish Date: 2022-10-21
Description:

Abstract

Biallelic loss-of-function variants in the SMG9 gene, encoding a regulatory subunit of the mRNA nonsense-mediated decay (NMD) machinery, are reported to cause heart and brain malformation syndrome. Here we report five patients from three unrelated families with intellectual disability (ID) and a novel pathogenic SMG9 c.551 T > C p.(Val184Ala) homozygous missense variant, identified using exome sequencing. Sanger sequencing confirmed recessive segregation in each family. SMG9 c.551T > C p.(Val184Ala) is most likely an autozygous variant identical by descent. Characteristic clinical findings in patients were mild to moderate ID, intention tremor, pyramidal signs, dyspraxia, and ocular manifestations. We used RNA sequencing of patients and age- and sex-matched healthy controls to assess the effect of the variant. RNA sequencing revealed that the SMG9 c.551T > C variant did not affect the splicing or expression level of SMG9 gene products, and allele-specific expression analysis did not provide evidence that the nonsense mRNA-induced NMD was affected. Differential gene expression analysis identified prevalent upregulation of genes in patients, including the genes SMOX, OSBP2, GPX3, and ZNF155. These findings suggest that normal SMG9 function may be involved in transcriptional regulation without affecting nonsense mRNA-induced NMD. In conclusion, we demonstrate that the SMG9 c.551T > C missense variant causes a neurodevelopmental disorder and impacts gene expression. NMD components have roles beyond aberrant mRNA degradation that are crucial for neurocognitive development.

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Series: European journal of human genetics
ISSN: 1018-4813
ISSN-E: 1476-5438
ISSN-L: 1018-4813
Volume: 30
Issue: 5
Pages: 619 - 627
DOI: 10.1038/s41431-022-01046-5
OADOI: https://oadoi.org/10.1038/s41431-022-01046-5
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Subjects:
Funding: We would like to thank all the families who participated in this study and Erja Pernu for recruiting the families. We also thank the Scribendi proofreading team for language editing. EJ was supported by the Academy of Finland (decision number 338446), the Maija, and Matti Vaskio Fund of the Finnish Medical Foundation. JM and ER were supported by the Competitive State Research Financing of the Expert Responsibility Area of Oulu University Hospital. AP was supported by the Academy of Finland Centre of Excellence in Complex Disease Genetics (Grant No. 312074, 336824) and Sigrid Juselius Foundation, EU/Horizon2020, COSYN, grant number 667301. MD was supported by 5U01MH111660-04, 04/10/17- 01/31/22, NIH/NIMH, The Autism Sequencing Consortium: Autism Gene Discovery in >50,000 Exomes. The sequencing of the Northern Finland Intellectual Disability cohort was funded by the US National Institutes of Health Grants U54HG003067, 5U01MH105669, and 5UM1HG008895. We thank the Broad Institute Genomics Platform for genomic data generation efforts. RNA sequencing was performed by the Sequencing Unit of FIMM Technology Centre, University of Helsinki. The FIMM Sequencing Unit is supported by Biocenter Finland.
Dataset Reference: De-identified materials, data sets, and protocols are available upon request. The reported variant was submitted to the LOVD database hosted at Leiden University Medical Center, the Netherlands.
Copyright information: © The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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