IRF4 haploinsufficiency in a family with Whipple’s disease

Antoine Guérin, Gaspard Kerner, Nico Marr, Janet G. Markle, Florence Fenollar, Natalie Wong, Sabri Boughorbel, Danielle T. Avery, Cindy S. Ma, Salim Bougarn, Matthieu Bouaziz, Vivien Beziat, Erika Della Mina, Tomi Lazarovt, Lisa Worley, Tina Nguyen, Etienne Patin, Caroline Deswarte, Rubén Martinez-Barricarte, Soraya BoucheritXavier Ayral, Sophie Edouard, Stéphanie Boisson-Dupuis, Vimel Rattina, Benedetta Bigio, Guillaume Vogt, Frédéric Geissmann, Lluis Quintana-Murci, Damien Chaussabel, Stuart G. Tangye, Didier Raoult, Laurent Abel, Jacinta Bustamante, Jean Laurent Casanova

Research output: Contribution to journalArticlepeer-review


The pathogenesis of Whipple’s disease (WD) remains largely unknown, as WD strikes only a very small minority of the individuals infected with Tropheryma whipplei (Tw). Asymptomatic carriage of Tw is less rare. We studied a large multiplex French kindred, containing four otherwise healthy WD patients (mean age: 76.7 years) and five healthy carriers of Tw (mean age: 55 years). We used a strategy combining genome-wide linkage analysis and whole-exome sequencing to test the hypothesis that WD is inherited in an autosomal dominant (AD) manner, with age-dependent incomplete penetrance. WD was linked to 12 genomic regions covering 27 megabases in the four patients. These regions contained only one very rare non-synonymous variation: the R98W variant of IRF4. The five Tw carriers were heterozygous for R98W. Interferon regulatory factor 4 (IRF4) is a transcription factor with pleiotropic roles in immunity. We showed that R98W was a loss-of-function allele, like only five other exceedingly rare IRF4 alleles of a total of 39 rare and common non-synonymous alleles tested. Furthermore, heterozygosity for R98W led to a distinctive pattern of transcription in leukocytes following stimulation with BCG or Tw. Finally, we found that IRF4 had evolved under purifying selection and that R98W was not dominant-negative, suggesting that the IRF4 deficiency in this kindred was due to haploinsufficiency. Overall, haploinsufficiency at the IRF4 locus selectively underlies WD in this multiplex kindred. This deficiency displays AD inheritance with incomplete penetrance, and chronic carriage probably precedes WD by several decades in Tw-infected heterozygotes.

Original languageEnglish (US)
JournalUnknown Journal
StatePublished - Oct 3 2017
Externally publishedYes


  • haploinsufficiency
  • IRF4
  • primary immunodeficiency
  • Whipple’s disease

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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