Association of rare variants in genes of immune regulation with pediatric autoimmune CNS diseases

Saba Jafarpour; Abhik Banerjee; Natalie K Boyd; Benjamin N Vogel; Kelli C Paulsen; Nusrat Ahsan; Wendy G Mitchell; Shafali S Jeste; Jonathan D Santoro

doi:10.1007/s00415-022-11325-2

Association of rare variants in genes of immune regulation with pediatric autoimmune CNS diseases

J Neurol. 2022 Dec;269(12):6512-6529. doi: 10.1007/s00415-022-11325-2. Epub 2022 Aug 12.

Authors

Saba Jafarpour¹, Abhik Banerjee², Natalie K Boyd¹, Benjamin N Vogel², Kelli C Paulsen¹, Nusrat Ahsan^{1

3}, Wendy G Mitchell^{1

3}, Shafali S Jeste^{1

3}, Jonathan D Santoro^{4

5

6}

Affiliations

¹ Children's Hospital Los Angeles, Los Angeles, CA, USA.
² Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³ Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁴ Children's Hospital Los Angeles, Los Angeles, CA, USA. santoroj@usc.edu.
⁵ Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. santoroj@usc.edu.
⁶ Division of Neurology, Children's Hospital Los Angeles, 4650 Sunset Blvd., MS82, Los Angeles, CA, 90027, USA. santoroj@usc.edu.

Abstract

Background: There is a gap in the literature regarding genetic underpinnings of pediatric autoimmune CNS diseases. This study explored rare gene variants implicated in immune dysregulation within these disorders.

Methods: This was a single-center observational study of children with inflammatory CNS disorder who had genetic testing through next generation focused exome sequencing targeting 155 genes associated with innate or adaptive immunity. For in silico prediction of functional effects of single-nucleotide variants, Polymorphism Phenotyping v2, and Sorting Intolerant from Tolerant were used, and Combined Annotation Dependent Depletion (CADD) scores were calculated. Identified genes were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.

Results: Of 54 patients, 42 (77.8%) carried variant(s), among which 12 (22.2%) had 3-8 variants. Eighty-eight unique single-nucleotide variants of 55 genes were identified. The most variants were detected in UNC13D, LRBA, LYST, NOD2, DOCK8, RNASEH2A, STAT5B, and AIRE. The majority of variants (62, 70.4%) had CADD > 10. KEGG pathway analysis revealed seven genes associated with primary immunodeficiency (Benjamini 1.40E - 06), six genes with NOD-like receptor signaling (Benjamini 4.10E - 04), five genes with Inflammatory Bowel Disease (Benjamini 9.80E - 03), and five genes with NF-kappa B signaling pathway (Benjamini 1.90E - 02).

Discussion: We observed a high rate of identification of rare and low-frequency variants in immune regulatory genes in pediatric neuroinflammatory CNS disorders. We identified 88 unique single-nucleotide variants of 55 genes with pathway analysis revealing an enrichment of NOD2-receptor signaling, consistent with involvement of the pathway within other autoinflammatory conditions and warranting further investigation.

Keywords: Autoimmune; Demyelinating; Genetics; Neuroinflammatory; Next-generation sequencing; Variants of unknown significance.

Publication types

Observational Study

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Autoimmune Diseases*
Central Nervous System Diseases*
Child
Exome Sequencing
Genetic Predisposition to Disease / genetics
Genetic Testing
Guanine Nucleotide Exchange Factors / genetics
Humans
Membrane Proteins / genetics
Nucleotides

Substances

Nucleotides
LRBA protein, human
Adaptor Proteins, Signal Transducing
UNC13D protein, human
Membrane Proteins
DOCK8 protein, human
Guanine Nucleotide Exchange Factors