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

Julia Macintosh; Alexa Derksen; Chantal Poulin; Nancy Braverman; Adeline Vanderver; Isabelle Thiffault; Steffen Albrecht; Geneviève Bernard

doi:10.1007/s10048-022-00683-8

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

Neurogenetics. 2022 Apr;23(2):151-156. doi: 10.1007/s10048-022-00683-8. Epub 2022 Jan 31.

Authors

Julia Macintosh^{1

2}, Alexa Derksen^{1

2}, Chantal Poulin^{1

3

4}, Nancy Braverman^{2

3

5

6}, Adeline Vanderver^{7

8}, Isabelle Thiffault^{9

10

11}, Steffen Albrecht¹², Geneviève Bernard^{13

14

15

16

17}

Affiliations

¹ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
² Child Health and Human Development Program, Research Institute of the McGill University Health Center, Montreal, QC, Canada.
³ Department of Pediatrics, McGill University, Montreal, QC, Canada.
⁴ Department of Pediatrics, Division of Pediatric Neurology, Montreal Children's Hospital, Montreal, QC, Canada.
⁵ Division of Medical Genetics, Montreal Children's Hospital, Montreal, QC, Canada.
⁶ Department of Human Genetics, McGill University, Montreal, QC, Canada.
⁷ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁸ Department of Neurology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Genomic Medicine Center, Children's Mercy Hospital, Kansas City, MO, USA.
¹⁰ University of Missouri Kansas City School of Medicine, Kansas City, MO, USA.
¹¹ Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO, USA.
¹² Department of Pathology, McGill University, Montreal, QC, Canada.
¹³ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada. genevieve.bernard@mcgill.ca.
¹⁴ Child Health and Human Development Program, Research Institute of the McGill University Health Center, Montreal, QC, Canada. genevieve.bernard@mcgill.ca.
¹⁵ Department of Pediatrics, McGill University, Montreal, QC, Canada. genevieve.bernard@mcgill.ca.
¹⁶ Department of Human Genetics, McGill University, Montreal, QC, Canada. genevieve.bernard@mcgill.ca.
¹⁷ Department Specialized Medicine, Division of Medical Genetics, McGill University Health Center, Montreal, QC, Canada. genevieve.bernard@mcgill.ca.

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.

Keywords: Exome sequencing; Intracranial calcifications; NRROS; Pediatric neurodegeneration.

Publication types

Case Reports
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Calcinosis* / genetics
Exome Sequencing
Humans
Macrophages / metabolism
Neurodegenerative Diseases* / genetics
Phenotype
White Matter*

Abstract

Publication types

MeSH terms

Grants and funding