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Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration

neurogenetics volume 23, pages 151–156 (2022)Cite this article

Abstract

Negative regulator of reactive oxygen species (NRROS) is a leucine-rich repeat protein expressed by microglia and perivascular macrophages. To date, 9 individuals have been reported with biallelic NRROS variants. Here, we report one individual with a severe neurodegenerative phenotype in which exome sequencing identified 2 novel variants in NRROS, a missense variant (c.185T>C, p.Leu62Pro) and a premature stop codon (c.310C>T, p.Gln104Ter). Pathological examination revealed both extensive grey and white matter involvement, dystrophic calcifications, and infiltration of foamy macrophages. This is the first reported case of NRROS variants with a mitochondrial ultrastructure abnormality noted on electron microscopy analysis of post-mortem tissue.

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The data supporting this study are included within the report.

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Acknowledgements

The authors wish to thank the patient and her family for their participation in this study. The authors also wish to acknowledge the McGill University and Genome Quebec Innovation Center.

Funding

This research was funded by research grants from the Canadian Institutes for Health Research (project grant 426534 and 201610PJT- 377869). This research was enabled in part by support provided by Compute Canada (www.computecanada.ca). JM is supported by Healthy Brains, Healthy Lives (HBHL) at McGill University. AD is funded by CIHR, Fondation du Grand Defi Pierre Lavoie and HBHL. AV is funded by the Kamens Chair in Translational Neurotherapeutics. 

G. Bernard has received the Clinical Research Scholar Junior 1 award from the Fonds de Recherche du Québec – Santé (FRQS) (2012–2016), the New Investigator Salary Award from the Canadian Institutes of Health Research (2017–2022) and the Clinical Research Scholar Senior award from the FRQS.

Author information

Authors and Affiliations

  1. Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

    Julia Macintosh, Alexa Derksen, Chantal Poulin & Geneviève Bernard

  2. Child Health and Human Development Program, Research Institute of the McGill University Health Center, Montreal, QC, Canada

    Julia Macintosh, Alexa Derksen, Nancy Braverman & Geneviève Bernard

  3. Department of Pediatrics, McGill University, Montreal, QC, Canada

    Chantal Poulin, Nancy Braverman & Geneviève Bernard

  4. Department of Pediatrics, Division of Pediatric Neurology, Montreal Children’s Hospital, Montreal, QC, Canada

    Chantal Poulin

  5. Division of Medical Genetics, Montreal Children’s Hospital, Montreal, QC, Canada

    Nancy Braverman

  6. Department of Human Genetics, McGill University, Montreal, QC, Canada

    Nancy Braverman & Geneviève Bernard

  7. Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Adeline Vanderver

  8. Department of Neurology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Adeline Vanderver

  9. Genomic Medicine Center, Children’s Mercy Hospital, Kansas City, MO, USA

    Isabelle Thiffault

  10. University of Missouri Kansas City School of Medicine, Kansas City, MO, USA

    Isabelle Thiffault

  11. Department of Pathology and Laboratory Medicine, Children’s Mercy Hospital, Kansas City, MO, USA

    Isabelle Thiffault

  12. Department of Pathology, McGill University, Montreal, QC, Canada

    Steffen Albrecht

  13. Department Specialized Medicine, Division of Medical Genetics, McGill University Health Center, Montreal, QC, Canada

    Geneviève Bernard

Authors
  1. Julia Macintosh
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  2. Alexa Derksen
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  3. Chantal Poulin
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  4. Nancy Braverman
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  5. Adeline Vanderver
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  6. Isabelle Thiffault
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  7. Steffen Albrecht
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  8. Geneviève Bernard
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Contributions

JM — Designed and conceptualized the study; acquisition of data; analysis and interpretation of data; drafted and revised the manuscript for intellectual content. AD — Acquisition of data; analysis and interpretation of data; revised the manuscript for intellectual content. CP — Acquisition of data and revised the manuscript for intellectual content. NB — Acquisition of data and revised the manuscript for intellectual content. AV — Acquisition of data and revised the manuscript for intellectual content. IT — Acquisition of data, analysis and interpretation of data; revised the manuscript for intellectual content. SA — Acquisition of data; analysis and interpretation of data; drafted and revised the manuscript for intellectual content. GB — Designed and conceptualized the study; acquisition of data; analysis and interpretation of data; drafted and revised the manuscript for intellectual content; study supervision.

Corresponding author

Correspondence to Geneviève Bernard.

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Ethics approval

Written informed consent from the legal representatives of the subject was obtained and the study was approved by the research ethics boards of the Montreal Children’s Hospital and the McGill University Health Center (11–105-PED, 2019–4972).

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The authors declare no competing interests.

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Cite this article

Macintosh, J., Derksen, A., Poulin, C. et al. Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration. Neurogenetics 23, 151–156 (2022). https://doi.org/10.1007/s10048-022-00683-8

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  • DOI: https://doi.org/10.1007/s10048-022-00683-8

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