Study 4 of 13BAM-15 literaturebiorxiv-preprint · Observational2026

<i>PTPN1</i> -related autoinflammation is a common cause of Aicardi-Goutières Syndrome with reduced penetrance

The study identifies PTPN1 variants in a subset of individuals with Aicardi-Goutières syndrome, suggesting a potential link to later-onset presentations and a higher prevalence of autoimmune disorders.

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Preclinical

Observational · this one

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Summary and findings

This study investigates the role of PTPN1 variants in Aicardi-Goutières syndrome (AGS) among individuals with suspected AGS. The authors identified 13 cases with PTPN1 variants in a cohort of 53 individuals (∼17%), with a median age of onset of 1.75 years. The findings suggest a connection between PTPN1 and later-onset AGS presentations.

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Median age of onset is 1.75 years (IQR 0.67), significantly later than other AGS genotypes (p<0.0001).2026

Abstract

The authors’ words, as biorxiv-preprint supplied them

<h4> Abstract </h4> <h4>Purpose</h4> Aicardi-Goutières syndrome (AGS) is a type I interferonopathy presently associated with nine genes. PTPN1 is a negative regulator of the interferon pathway previously associated with chronic inflammation and recently type 1 IFN autoinflammation. <h4>Methods</h4> Genomic data from undiagnosed individuals with suspected AGS were interrogated for PTPN1 variants, and predicted loss-of-function (pLOF) and damaging missense variants in PTPN1 were sought in two additional academic databases as well as the All of Us database. <h4>Results</h4> We identified 13 cases with ultra-rare heterozygous pLOF or highly damaging missense variants in PTPN1 . Nine cases were identified in a cohort of 53 individuals (∼ 17%) with clinical, imaging and persistent biochemical features of AGS. Median age of onset is 1.75 years (IQR 0.67), significantly later (p< 0.0001) than other AGS genotypes. Four additional cases were identified in academic datasets with variable clinical features suggestive of autoinflammation. Additionally, 49 individuals with ultra-rare, damaging PTPN1 variants were identified in the All of Us database, none had features suggestive of AGS, but autoimmunity was highly prevalent (∼21.6%). <h4>Conclusion</h4> Our data implicate PTPN1 as a cause of later-onset presentations of AGS within a broader spectrum of autoinflammatory phenotypes. Segregation and biobank data demonstrate reduced penetrance, with carriers being enriched for autoimmune disorders.

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