Trifiletti R, Lachman HM, Manusama O, Zheng D, Spalice A, Chiurazzi P, Schornagel A, Serban AM, van Wijck R, Cunningham JL, Swagemakers S, van der Spek PJ. Identification of ultra-rare genetic variants in pediatric acute onset neuropsychiatric syndrome (PANS) by exome and whole genome sequencing. Sci Rep. 2022 Jun 30;12(1):11106. doi: 10.1038/s41598-022-15279-3. PMID: 35773312. – Open Access
- The pathological mechanisms are likely heterogeneous, but we hypothesize convergence on one or more biological pathways.
- Conducted whole exome sequencing (WES) on a U.S. cohort of 386 cases, and whole genome sequencing (WGS) on ten cases from the European Union who were selected because of severe PANS.
- Focused on identifying potentially deleterious genetic variants that were de novo or ultra‑rare (MAF) < 0.001. Candidate mutations were found in 11 genes (PPM1D, SGCE, PLCG2, NLRC4, CACNA1B, SHANK3, CHK2, GRIN2A, RAG1, GABRG2, and SYNGAP1) in 21 cases, which included two or more unrelated subjects with ultra‑rare variants in four genes.
- These genes converge into two broad functional categories.
- One regulates peripheral immune responses and microglia (PPM1D, CHK2, NLRC4, RAG1, PLCG2).
- The other is expressed primarily at neuronal synapses (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNA1B, SGCE). Mutations in these neuronal genes are also described in autism spectrum disorder and myoclonus‑dystonia.
- 12/21 cases developed PANS superimposed on a preexisting neurodevelopmental disorder. Genes in both categories are also highly expressed in the enteric nervous system and the choroid plexus.
- Thus, genetic variation in PANS candidate genes may function by disrupting peripheral and central immune functions, neurotransmission, and/or the blood‑CSF/brain barriers following stressors such as infection