Ultrarare Variants in DNA Damage Repair and Mitochondrial Genes in Pediatric Acute-Onset Neuropsychiatric Syndrome and Acute Behavioral Regression in Neurodevelopmental Disorders

SUMMARY

This study examined ultrarare genetic variants in 32 children and adolescents with pediatric acute-onset neuropsychiatric syndrome (PANS), autism spectrum disorder (ASD) with behavioral regression, and other neurodevelopmental disorders (NDDs). Using whole-exome and whole-genome sequencing, the investigators identified pathogenic or likely pathogenic variants in genes involved in several biologically relevant pathways, including DNA damage response and repair, mitochondrial function, innate immune signaling, and gut immune regulation. Variants in DNA damage response pathways were found in genes responsible for genomic stability, chromatin regulation, DNA repair, and interferon signaling, while additional cases showed variants affecting mitochondrial DNA maintenance and mitophagy. Other variants were identified in genes involved in gut barrier integrity and immune regulation within the gastrointestinal tract.

The authors propose that impaired DNA repair and mitochondrial dysfunction may contribute to neuropsychiatric deterioration by promoting accumulation of cytosolic DNA and activation of innate immune pathways such as cGAS-STING, AIM2 inflammasome signaling, and type I interferon responses. These pathways may be further amplified during infectious or inflammatory stressors, potentially contributing to the abrupt onset and episodic worsening observed in PANS and related regression syndromes. The study also reports a high prevalence of autoimmune and autoinflammatory disorders in affected families, supporting a model of shared genetic susceptibility interacting with environmental triggers.

Importantly, these findings extend prior observations linking immune dysregulation, neuroinflammation, and infection-associated neuropsychiatric symptoms with genetic variation in pathways regulating genomic stability and mitochondrial integrity. The identification of likely pathogenic variants in genes involved in gut barrier and microbiome-associated immune regulation suggests that gut–immune interactions may also contribute to symptom expression in a subset of patients. Overall, the study supports biologically grounded mechanisms underlying infection-associated neuropsychiatric deterioration and highlights the potential for future research integrating genetics, immunophenotyping, and functional studies to define biologically distinct subgroups and inform more targeted therapeutic approaches for PANS, PANDAS, and related neuroimmune neuropsychiatric conditions.

LINK TO PAPER: https://doi.org/10.1159/000550301