PTPN1-related autoinflammation is a common cause of Aicardi-Goutières Syndrome with reduced penetrance.
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Calame Daniel G, Wiener Emma K, Gavazzi Francesco, Sevagamoorthy Anjana, Pizzino Amy, Arnold Kaley, Dominguez Gonzalez Carlos, Jammihal Tejas, Bennett Mariko, Adang Laura, Woidill Sarah, Whitehead Matthew T, Vossough Arastoo, D'Aiello Russell, Takanohashi Asako, Lele Janhavi, Simons Cas, Rius Rocio, Formaini Edward, Sullivan Kathleen E, Andzelm Milena, Ebrahimi-Fakhari Darius, Otten Catherine, Wong Stephen, Reynolds Thomas, Schiffmann Raphael, Wolf Nicole I, Waisfisz Quinten, Niermeijer Jikke-Mien, DeMarzo Danielle, Dawood Moez, Gandhi Mira, Levine Jesse M, Chinn Ivan K, Fisher Kristen, Emrick Lisa, Alam Chadi Al, Kaiyrzhanov Rauan, Maroofian Reza, Houlden Henry, Jhangiani Shalini N, Mehta Heer H, Muzny Donna M, Sedlazeck Fritz J, Posey Jennifer E, Lupski James R, Gibbs Richard A, Rajagopalan Ramakrishnan, Vanderver Adeline
Аннотация
METHODS: 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.
RESULTS: 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%).
CONCLUSION: 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.