The common HAQ STING allele prevents clinical penetrance of COPA syndrome

Noa Simchoni¹, Shogo Koide², Maryel Likhite³, Yoshihiko Kuchitsu², Senkottuvelan Kadirvel⁴, Christopher S Law¹, Brett M Elicker⁵, Santosh Kurra¹, Margaret Mei-Kay Wong³, Bo Yuan^{4

6}, Alice Grossi⁷, Ronald M Laxer^{8

9}, Stefano Volpi^{10

11}, Dilan Dissanayake⁸, Tomohiko Taguchi², David B Beck^{3

12}, Tiphanie P Vogel^{13

14}, Anthony K Shum^{1

15}

Affiliations

¹ Division of Pulmonary, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
² Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
³ Center for Human Genetics and Genomics, NYU Grossman School of Medicine , New York, NY, USA.
⁴ Human Genome Sequencing Center, Baylor College of Medicine , Houston, TX, USA.
⁵ Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.
⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁷ Laboratorio Genetica e Genomica Delle Malattie Rare, Istituto Giannina Gaslini , Genoa, Italy.
⁸ Division of Rheumatology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
⁹ Division of Rheumatology, Department of Medicine, St. Michael's Hospital, Toronto, Canada.
¹⁰ Unità Operativa Complessa Reumatologia e Malattie Autoinfiammatorie, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Giannina Gaslini , Genoa, Italy.
¹¹ Dipartimento Di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Università Degli Studi Di Genova , Genoa, Italy.
¹² Division of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA.
¹³ Division of Rheumatology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
¹⁴ Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, USA.
¹⁵ Cardiovascular Research Institute, University of California, San Francisco , San Francisco, CA, USA.

PMID: 40014299
PMCID: PMC11867111 (available on 2026-02-27)
DOI: 10.1084/jem.20242179

The common HAQ STING allele prevents clinical penetrance of COPA syndrome

Noa Simchoni et al. J Exp Med. 2025.

. 2025 Apr 7;222(4):e20242179.

doi: 10.1084/jem.20242179. Epub 2025 Feb 27.

Authors

Affiliations

¹ Division of Pulmonary, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
² Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
³ Center for Human Genetics and Genomics, NYU Grossman School of Medicine , New York, NY, USA.
⁴ Human Genome Sequencing Center, Baylor College of Medicine , Houston, TX, USA.
⁵ Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.
⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁷ Laboratorio Genetica e Genomica Delle Malattie Rare, Istituto Giannina Gaslini , Genoa, Italy.
⁸ Division of Rheumatology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
⁹ Division of Rheumatology, Department of Medicine, St. Michael's Hospital, Toronto, Canada.
¹⁰ Unità Operativa Complessa Reumatologia e Malattie Autoinfiammatorie, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Giannina Gaslini , Genoa, Italy.
¹¹ Dipartimento Di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Università Degli Studi Di Genova , Genoa, Italy.
¹² Division of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA.
¹³ Division of Rheumatology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
¹⁴ Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, USA.
¹⁵ Cardiovascular Research Institute, University of California, San Francisco , San Francisco, CA, USA.

PMID: 40014299
PMCID: PMC11867111 (available on 2026-02-27)
DOI: 10.1084/jem.20242179

Abstract

COPA syndrome, an autosomal-dominant inborn error of immunity, is nonpenetrant in ∼20% of individuals, with no known mediators of protection. Recent studies implicate STING in the pathogenesis of COPA syndrome. We show that the common HAQ STING allele mediates complete clinical protection. We sequenced 35 individuals with COPA mutations, 26 affected patients and 9 unaffected carriers, finding HAQ STING co-segregation with clinical nonpenetrance. Exome sequencing identified only the mutations comprising HAQ STING as variants shared by unaffected carriers and absent in patients. Experimentally, we found that HAQ STING acts dominantly to dampen COPA-dependent STING signaling. Expressing HAQ STING in patient cells rescued the molecular phenotype of COPA syndrome. Our study is the first report of a common and well-tolerated allele mediating complete clinical protection from a severe genetic disorder. Our findings redefine the diagnostic criteria for COPA syndrome, expose functional differences among STING alleles with broad scientific and clinical implications, and reveal a potential universal gene therapy approach for patients.

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Conflict of interest statement

Disclosures: N. Simchoni reported a patent to HAQ STING gene therapy for COPA syndrome pending. C.S. Law reported a patent to HAQ STING gene therapy for COPA syndrome pending. M.M.-K. Wong reported owning GeneDx stock (105 shares). R.M. Laxer reported “other” from Eli Lilly, Sanofi, Novartis, Sobi, and Akros Pharma outside the submitted work. D.B. Beck reported personal fees from Sobi, Novartis, GSK, Alexion, and Genesis Therapeutics outside the submitted work. T.P. Vogel reported personal fees from SOBI, Pfizer, Moderna, and Novartis, and “other” from AstraZeneca outside the submitted work, and being a member of the scientific advisory board of the COPA Syndrome Foundation. A.K. Shum reported a patent to HAQ STING gene therapy for COPA syndrome pending. No other disclosures were reported.

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The common HAQ STING allele prevents clinical penetrance of COPA syndrome

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The common HAQ STING allele prevents clinical penetrance of COPA syndrome

Authors

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Abstract

Conflict of interest statement

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