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Abstract Details

Potential Role of Variants of UNC13D in Pediatric Autoimmune CNS Disorders
Autoimmune Neurology
S3 - Autoimmune Neurology 1: Mechanisms of Disease, Clinical Practice (2:48 PM-3:00 PM)
Immune system dysregulation gives rise to a broad range of autoimmune diseases. Rare variants of alleles in genes implicated in primary immune dysregulation could have a potential role in autoimmune CNS disorders although are infrequently tested.  

To identify variants of immune dysregulation genes with potential role in pediatric autoimmune central nervous system (CNS) disorders.

We assessed consecutive patients with autoimmune CNS diseases who had undergone genetic analysis with the Invitae Autoinflammatory Syndromes panel. This panel evaluates 155 genes associated with primary autoimmune disorders without CNS involvement.

Fifty patients were included (42% male, median age 15, IQR 9.25-17, range 2-21 years). Fourteen patients (28%) had multiple sclerosis (MS), 13 (26%) had Myelin oligodendrocyte glycoprotein associated disorder (MOGAD), 5 (10%) had autoimmune encephalitis, and 4 (8%) CNS vasculitis. Heterozygous variants of unknown significance of 66 genes were identified in 37 patients (72%). Most frequently affected genes included UNC13D (5, 10% of patients), NOD2 (4, 8%), LRBA (3, 6%), and RNASEH2A (3, 6%). Patients with UNC13D single nucleotide variants presented with MOGAD (2/5), MS (1/5) and CNS vasculitis (2/5). All these patients had variants in one or more other genes of immune dysregulation, including STXBP2. Homozygous variants of UNC13D and STXBP2 are associated with familial Hemophagocytic lymphohistiocytosis (HLH) although heterozygous mutations are of unknown significance.

We observed a high prevalence (72%) of potentially contributing variants in this cohort of pediatric neuroinflammatory disorders. Pathogenic variants of UNC13D are associated with NK degranulation dysfunction resulting in familial HLH, and heterozygous variants have been described in other immune dysregulation disorders including with severe cytokine storm with COVID-19 infection. Given the striking prevalence of variants in UNC13D in this population, further study is necessary.
Saba Jafarpour (Children’s Hospital of Los Angeles)
Dr. Jafarpour has nothing to disclose.
Nusrat Ahsan Dr. Ahsan has nothing to disclose.
Jonathan Santoro (Department of Neurology, Children's Hospital Los Angeles) Dr. Santoro has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for UCB. Dr. Santoro has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Cycle Pharma.