DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency


  • T. Volk
  • U. Pannicke
  • I. Reisli
  • A. Bulashevska
  • J. Ritter
  • A. Björkman
  • A.A. Schäffer
  • M. Fliegauf
  • E.H. Sayar
  • U. Salzer
  • P. Fisch
  • D. Pfeifer
  • M. Di Virgilio
  • H. Cao
  • F. Yang
  • K. Zimmermann
  • S. Keles
  • Z. Caliskaner
  • S.Ü. Güner
  • D. Schindler
  • L. Hammarström
  • M. Rizzi
  • M. Hummel
  • Q. Pan-Hammarstroem
  • K. Schwarz
  • B. Grimbacher


  • Human Molecular Genetics


  • Hum Mol Genet 24 (25): 7361-7372


  • Null mutations in genes involved in V(D)J recombination cause a block in B- and T- cell development, clinically presenting as severe combined immunodeficiency (SCID). Hypomorphic mutations in the non-homologous end joining gene DCLRE1C (encoding ARTEMIS) have been described to cause atypical SCID, Omenn syndrome, Hyper IgM syndrome and inflammatory bowel disease - all with severely impaired T-cell immunity. By whole-exome sequencing, we investigated the molecular defect in a consanguineous family with three children clinically diagnosed with antibody deficiency. We identified perfectly segregating homozygous variants in DCLRE1C in three index patients with recurrent respiratory tract infections, very low B cell numbers and serum IgA levels. In patients, decreased colony survival after irradiation, impaired proliferative response, and reduced counts of naïve T cells were observed in addition to a restricted T cell receptor repertoire, increased palindromic nucleotides in the complementarity determining regions 3, and long stretches of microhomology at switch junctions. Defective V(D)J recombination was complemented by wild-type ARTEMIS protein in vitro. Subsequently, homozygous or compound heterozygous DCLRE1C mutations were identified in nine patients from the same geographic region. We demonstrate that DCLRE1C mutations can cause a phenotype presenting as only antibody deficiency. This novel association broadens the clinical spectrum associated with ARTEMIS mutations. Clinicians should consider the possibility that an immunodeficiency with a clinically mild initial presentation could be a combined immunodeficiency, so as to provide appropriate care for affected patients.