PTPN1 variants identified in 17% of AGS cohort with later onset and reduced penetranceCould a common gene variant explain some cases of a rare childhood brain disease?

medRxiv Published April 5, 2026 Study authors: Calame, D. G.; Wiener, E.; Gavazzi, F.; Sevagamoorthy, A.; Pizzino, A.; Arnold, K.; Gonzalez, C. D.;… DOI ↗ Editorial oversight: Dr. Ji-eun Park, MD · Brain, Mind & Pain

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Key Takeaway

Consider PTPN1 variants in AGS with later onset, but recognize reduced penetrance and association-only evidence.

This genomic cohort study interrogated databases to investigate PTPN1 variants in autoinflammation. Researchers analyzed 13 cases with PTPN1 variants from genomic data, including 9 cases from a cohort of 53 individuals with AGS features (~17%), plus 4 cases from academic datasets and 49 individuals with PTPN1 variants from the All of Us database. The exposure was presence of ultra-rare heterozygous predicted loss-of-function or damaging missense variants in PTPN1.

In the AGS cohort, PTPN1 variants were identified in 9 of 53 individuals (approximately 17%). Median age of onset for PTPN1-related AGS was 1.75 years (IQR 0.67), which was significantly later than other AGS genotypes (p<0.0001). Among 49 PTPN1 variant carriers in the All of Us database, autoimmunity was highly prevalent (~21.6%), but none had features suggestive of AGS (0/49).

Safety and tolerability data were not reported. Key limitations were not explicitly reported, though the observational nature, cohort specificity, and lack of follow-up data constrain interpretation. The study demonstrates association rather than causation and observes reduced penetrance, meaning many carriers do not develop AGS. Practice relevance is not established; these findings require validation in independent cohorts before clinical application.

When a child develops a rare, severe brain disease like Aicardi-Goutieres syndrome (AGS), finding the genetic cause can be a long and painful journey for families. A new study looked at people with suspected AGS and found that variants in a specific gene, PTPN1, were present in about 17% of a small group of 53 individuals. This suggests PTPN1 could be a new genetic cause for some cases.

The study involved looking at genetic data from people with AGS features, academic databases, and a large public database called All of Us. They found that in people with AGS, the disease started later—around 1.75 years old—compared to other known genetic forms. Interestingly, when they looked at people with the PTPN1 variant in the general population, none showed signs of AGS, but about 22% had other autoimmune conditions.

This is a key point: having the PTPN1 variant doesn't guarantee someone will get AGS. The researchers observed 'reduced penetrance,' meaning many carriers of the variant never develop the full disease. The study only shows an association, not a direct cause. It was an observational look at genetic data from specific groups, so we don't know how well these findings apply to everyone. For now, it offers a new piece of the puzzle for doctors and families searching for answers.

What this means for you:

A gene variant is linked to some cases of a rare brain disease, but many carriers never get sick.

Study Details

Study typeCohort

EvidenceLevel 3

PublishedApr 2026

View Original Abstract ↓

AbstractO_ST_ABSPurposeC_ST_ABSAicardi-Goutieres 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. MethodsGenomic 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. ResultsWe 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%). ConclusionOur 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.

PTPN1 variants identified in 17% of AGS cohort with later onset and reduced penetranceCould a common gene variant explain some cases of a rare childhood brain disease?

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PTPN1 variants identified in 17% of AGS cohort with later onset and reduced penetranceCould a common gene variant explain some cases of a rare childhood brain disease?

Study Details

Intravenous tenecteplase improves functional outcomes but increases hemorrhage risk in non-large vessel occlusion acute ischemic stroke

Tenecteplase improves stroke recovery but increases bleeding risk in late treatment window

Clinical research that matters. Delivered to your inbox.

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