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[Preprint]. 2025 Aug 27:2025.08.27.25333852.
doi: 10.1101/2025.08.27.25333852.

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

Dhanya Vettiatil  1 , Anjana Soorajkumar  1 , Robert A Dubin  2 , Erika Pedrosa  1 , Allan Schornagel  3 , John S Lambert  4 , Isadora Pinheiro Costa  1 , Joseph McDonald  5 , Sigrid M A Swagemakers  6 , Peter J van der Spek  6 , Jennifer Frankovich  7 , Janet L Cunningham  8 , Herbert M Lachman  1   9
Affiliations

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

Dhanya Vettiatil et al. medRxiv. .

Update in

Abstract

Introduction: We recently identified variants in 10 genes that are members of either the p53 pathway or Fanconi Anemia Complex (FAC), regulators of the DNA repair (DNA damage response; DDR) in 17 cases with Pediatric Acute-Onset Neuropsychiatry Syndrome (PANS) or regression in autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDD). We aimed to identify additional cases with genetic vulnerabilities in DDR and related pathways.

Methods: Whole exome sequencing (WES) and whole genome sequencing (WGS) data from 32 individuals were filtered and analyzed to identify ultrarare pathogenic or likely pathogenic variants.

Results: Variants affecting DDR were found in 14 cases diagnosed with PANS or regression (CUX1, USP45, PARP14, UVSSA, EP300, TREX1, SAMHD1, STK19, MYTl1, TEP1, PIDD1, ADNP, FANCD2, and RAD54L). The CUX1 variant is de novo, as are two cases who had mutations in genes that affect mitochondrial functions that are connected directly or indirectly to mitophagy (PRKN and POLG), which can trigger the same innate immune pathways when disrupted as abnormal DDR. We also found pathogenic or likely pathogenic secondary mutations in several genes that are primarily expressed in the gut that have been implicated in gut microbiome homeostasis (e.g., LGALS4, DUOX2, CCR9).

Conclusion: These findings align with previous genetic findings and strengthen the hypothesis that abnormal DDR and mitochondrial dysfunction underly pathogenic processes in neuropsychiatric decompensation. The potential involvement of genetic variants in gut microbiome homeostasis is a novel aspect of our study. Functional characterization of the downstream impact of DDR deficits may point to novel treatment strategies.

Keywords: CCR9; DNA damage response; DNA repair; DUOX2; Fanconi anemia complex; Jansen de Vries Syndrome; PANS; autism; cGAS-STING; gut microbiome; neuroinflammation; neuroinflammatory; p53; regression; type I interferons.

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Conflict of interest statement

Conflict of Interest Statement J.L.C. has received lecturing fees from Otsuka Pharma Scandinavia, Janssen-Cilag AB and H. Lundbeck AB.

Figures

Figure :
Figure :. Protein–protein interaction (PPI) analysis.
Shows relationships among the DNA repair and mitochondrial genes described in this paper, along with those found in our previous studies [1, 38]. See methods section for details
See this image and copyright information in PMC

References

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