Clémence Bégo David, Tifenn Wauquier, Alix de Becdelièvre, C. Louvrier, Maud Tusseau, Cécile Masson, Luís Seabra, Caroline Kannengiesser, Hayssam Al Arab, Ibrahima Ba, Mary Brennan, Alexandre Belot, Nadia Nathan, Hélène Maillard, Héloïse Reumaux, Jérémie Sellam, Jacques Cadranel, Yves Hatchuel, Laurence Weiss, Sébastien De Almeida, Cinthia Rames, Marie Wislez, C. Vigier, Géraldine Labouret, Claire Kastner, François Provôt, Julien Tarabeux, Elise Schaefer, Darragh Duffy, Vincent Bondet, P. Bastard, Anne Puel, Jean-Laurent Casanova, Gillian I. Rice, Brigitte Bader-Meunier, Yanick J. Crow, Alice Lepelley, Marie-Louise Frémond
COPA syndrome is a rare monogenic autoinflammatory disease due to heterozygous mutations in COPA, encoding the coatomer subunit α. COPA syndrome demonstrates phenotypic overlap with STING-associated vasculopathy with onset in infancy (SAVI), the latter due to gain-of-function mutations in STING1. Indeed, STING activation is a key driver of the pathogenesis of COPA syndrome, and a recent report suggested that the presence of the common HAQ STING allele confers complete protection against the development of clinical disease in the context of pathogenic heterozygous mutations in COPA. Given the potential significance of this result for patient management, we investigated the STING HAQ haplotype status of a separate cohort of individuals segregating pathogenic mutations in COPA. In doing so, we ascertained five HAQ-negative, clinically asymptomatic individuals aged 30, 39, 39, 42, and 43 years at last evaluation, and an HAQ-positive male with kidney disease that we consider most likely attributable to the recurrent R233H mutation in COPA. Our findings challenge the suggestion that STING haplotype status is the sole determinant of clinical penetrance in COPA syndrome.