Ultrarare Variants in DNA Damage Repair Genes in Pediatric Acute-Onset Neuropsychiatric Syndrome or Acute Behavioral Regression in Neurodevelopmental Disorders
Cunningham, J. L.; Frankovich, J.; Dubin, R. A.; Pedrosa, E.; Nur Baykara, R.; Schlenk, N. C.; Maqbool, S.; Dolstra, H.; Marino, J.; Edinger, J.; Shea, J.; Laje, G.; Swagermakers, S. M. A.; Sinnadurai, S.; van der Spek, P.; Lachman, H. M.
Show abstract
Acute onset of severe psychiatric symptoms or regression may occur in children with premorbid neurodevelopmental disorders, although typically developing children can also be affected. Infections or other stressors are likely triggers. The underlying causes are unclear, but a current hypothesis suggests the convergence of genes that influence neuronal and immunological function. We previously identified 11 genes in Pediatric Acute-Onset Neuropsychiatry Syndrome (PANS), in which two classes of genes related to either synaptic function or the immune system were found. Among the latter, three affect the DNA damage response (DDR): PPM1D, CHK2, and RAG1. We now report an additional 17 cases with mutations in PPM1D and other DDR genes in patients with acute onset of psychiatric symptoms and/or regression that were classified by their clinicians as PANS or another inflammatory brain condition. The genes include clusters affecting p53 DNA repair (PPM1D, ATM, ATR, 53BP1, and RMRP), and the Fanconi Anemia Complex (FANCE, SLX4/FANCP, FANCA, FANCI, and FANCC). We hypothesize that defects in DNA repair genes, in the context of infection or other stressors, could lead to an increase in cytosolic DNA in immune cells triggering DNA sensors, such as cGAS-STING and AIM2 inflammasomes. These findings could lead to new treatment strategies.
Matching journals
The top 9 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Chromosome X-Wide Common Variant Association Study (XWAS) in Autism Spectrum Disorder 92%
- A recurrent de novo splice site variant involving DNM1 alternative exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism 92%
- Rare variants in PRKCI cause Van der Woude syndrome and other features of peridermopathy 92%
Similar papers in this journal
- Brain Extracellular Matrix implications in multiple neurological disorders are revealed through a meta-analysis of transcriptional changes 91%
- Neurodevelopmental defects in Dravet syndrome Scn1a+/- mice: targeting GABA-switch rescues behavioral dysfunctions but not seizures and mortality. 90%
- Intersecting impact of CAG repeat and Huntingtin knockout in stem cell-derived cortical neurons 89%
Similar papers in this journal
Similar papers in this journal
- Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes 92%
- Mendelian gene identification through mouse embryo viability screening 91%
- STRchive: a dynamic resource detailing population-level and locus-specific insights at tandem repeat disease loci 90%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.