Background/Purpose: Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) is characterized by sudden-onset OCD and additional neuropsychiatric symptoms. Imaging studies point to inflammation in the basal ganglia as a potential driver of the psychiatric symptoms. Patients with PANS also develop other co-morbid inflammatory disorders (i.e., arthritis, thyroiditis, celiac disease, etc.). Like other autoimmune diseases, during PANS disease flares, patients have high levels of the C4 split product, which is consistent with activation of this pathway. Since there is emerging evidence for copy number variations in the C4 gene which presents with symptoms that effect the brain, we wanted to know whether patients with PANS have vulnerability for this illness due to aberrant copy numbers of the C4 gene in their genome.

Methods: We characterized the complex genotype of the C4 gene-complex using digital-droplet PCR for 279 patients with PANS (collected at three different sites in the United States) and a comparable number of controls from a random subset of healthy controls from the Molecular Genetics in Schizophrenia Cohort (Gejman Nature Genetics 2008) and Genomic Psychiatry Cohort (Pato, Sobell, et al. A J Med Genet B Neuropsychatr Genet. 2013). Specifically, the numbers of C4 genes and their sub forms (AS, AL, BS and BL) were enumerated. The specific copy numbers of each of these genes were compared between the patient and control groups using Mann-Whitney U-test (to handle the expected skewed distribution of copies). To test whether the proportion of children with long inactive HERV insert differs in the PANS and healthy control cohorts, we used a Fisher’s exact test.

Results: Overall, the patient cohort had fewer total number of copies of the C4 gene in their genome (p=0.03), specifically in C4BL gene copies (p< 0.001) where the patient group had 0-3 copies compared to 0-5 copies in the control group. The total number of C4B genes was also reduced in the patient cohort.

Conclusion: We show, for the first time, a lower copy number of complement genes in patients who meet strict criteria for PANS compared to healthy controls. Fewer copy numbers of the C4 gene appear to be attributed to lower copy numbers of the long-form of the C4B gene. These findings will need to be confirmed in an independently collected cohort as well as explored in patients with different racial/ethnic backgrounds.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/low-c4-copy-number-of-total-c4-gene-c4b-gene-and-c4bl-gene-in-children-with-pediatric-acute-onset-neuropsychiatric-syndrome-pans/