TY - JOUR
T1 - Identification of ultra-rare genetic variants in pediatric acute onset neuropsychiatric syndrome (PANS) by exome and whole genome sequencing
AU - Trifiletti, Rosario
AU - Lachman, Herbert M.
AU - Manusama, Olivia
AU - Zheng, Deyou
AU - Spalice, Alberto
AU - Chiurazzi, Pietro
AU - Schornagel, Allan
AU - Serban, Andreea M.
AU - van Wijck, Rogier
AU - Cunningham, Janet L.
AU - Swagemakers, Sigrid
AU - van der Spek, Peter J.
N1 - Funding Information:
This research is supported by the National Natural Science Foundation of China (12101433), and the Two-Way Support Programs of Sichuan Agricultural University (1921993077).
Funding Information:
The authors want to thank EXPAND for directing researchers to PANS cases throughout the European Union, and Erika Pedrosa and Stefanie Mittelstadt for copy editing the manuscript. HML is supported by the National Institute of Child Health and Human Development NIH/NICHD; P30 HD071593 to the Albert Einstein College of Medicine’s Rose F. Kennedy Intellectual and Developmental Disabilities Research Center. The Lachman lab also receives support from the Janice C. Blanchard Family Fund. P.J. van der Spek is supported by EU H2020 grants, an ImmunAID grant (ID: 7792950), and a MOODSTRATIFICATION grant (ID: 754740). The Bioinformatics infrastructure and team is supported by grants from KWF, NWO/ZonMW and the Dutch Heart foundation through the BDVA initiated H2020 Bigmedilytics program on Personalized Medicine. Janet Cunningham is a Gullstrand Fellow at Uppsala University Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors dedicate this paper to Dr. Paul Janssen whose ideas about the role of the immune system in tics and psychosis help form the framework for this research project, and to participating families for their courage and support.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Abrupt onset of severe neuropsychiatric symptoms including obsessive–compulsive disorder, tics, anxiety, mood swings, irritability, and restricted eating is described in children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). Symptom onset is often temporally associated with infections, suggesting an underlying autoimmune/autoinflammatory etiology, although direct evidence is often lacking. The pathological mechanisms are likely heterogeneous, but we hypothesize convergence on one or more biological pathways. Consequently, we 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. We 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. In fact, 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.
AB - Abrupt onset of severe neuropsychiatric symptoms including obsessive–compulsive disorder, tics, anxiety, mood swings, irritability, and restricted eating is described in children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). Symptom onset is often temporally associated with infections, suggesting an underlying autoimmune/autoinflammatory etiology, although direct evidence is often lacking. The pathological mechanisms are likely heterogeneous, but we hypothesize convergence on one or more biological pathways. Consequently, we 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. We 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. In fact, 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.
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U2 - 10.1038/s41598-022-15279-3
DO - 10.1038/s41598-022-15279-3
M3 - Article
C2 - 35773312
AN - SCOPUS:85133298326
VL - 12
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 11106
ER -