Dr. Rosario R. Trifiletti, MD PhD

We carried out whole exome sequencing (WES) on a U.S. cohort of 383 patients who met diagnostic criteria for PANS, including 133 family triads, We focused on identifying potentially deleterious genetic variants that were either de novo or ultra-rare with a minor allele frequency {MAF) < 0.001. Candidate variants were found in 11 genes: PPM1D, SGCE, PLCG2, NLRC4, CACNA18, SHANK3, CHK2, GRIN2A, RAG1, GABRG2, and SYNGAP1 in a total of 19 patients, which included two or more unrelated subjects with ultra-rare variants in SGCE, NLRC4 and SHANK3, and two whose encoded proteins interact with each other: PPM1D and CHK2. The PANS candidate genes we uncovered separate into two functional categories. One group regulates peripheral innate and adaptive immune responses, some of which influence microglia function (PPM1D, CHK2, NLRC4, RAG1, PLCG2). Another is expressed primarily at neuronal synapses or affect synaptic function (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNAlB, SGCE). Five of the genes implicated in PANS have also been implicated in autism, according to the SFARI Gene database. These are PPMlD, CACNAlB, SHANK3, GRIN2A, and SYNGAPl, which are genes that tend to affect neuronal synapses rather than immune function. We performed a correlation of "log of odds" (LOD) scores for over 3,000 genes and found a robust correlation between PANS and autism LOD scores. Taken as a whole, this data suggests that is considerable overlap between genes predisposing to PANS and those predisposing to autism, and may explain why the incidence of PANS is some 10-20 fold higher in children with autism than in neurotypical patients. These data also suggest that every child diagnosed with autism ought to be evaluated for PANS to identify a potentially treatable inflammatory component.