Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

Asbjørg Stray-Pedersen, Hanne Sørmo Sorte, Pubudu Samarakoon, Tomasz Gambin, Ivan K. Chinn, Zeynep H. Coban Akdemir, Hans Christian Erichsen, Lisa R. Forbes, Shen Gu, Bo Yuan, Shalini N. Jhangiani, Donna M. Muzny, Olaug Kristin Rødningen, Ying Sheng, Sarah K. Nicholas, Lenora M. Noroski, Filiz O. Seeborg, Carla M. Davis, Debra L. Canter, Emily M. MaceTimothy J. Vece, Carl E. Allen, Harshal A. Abhyankar, Philip M. Boone, Christine R. Beck, Wojciech Wiszniewski, Børre Fevang, Pål Aukrust, Geir E. Tjønnfjord, Tobias Gedde-Dahl, Henrik Hjorth-Hansen, Ingunn Dybedal, Ingvild Nordøy, Silje F. Jørgensen, Tore G. Abrahamsen, Torstein Øverland, Anne Grete Bechensteen, Vegard Skogen, Liv T.N. Osnes, Mari Ann Kulseth, Trine E. Prescott, Cecilie F. Rustad, Ketil R. Heimdal, John W. Belmont, Nicholas L. Rider, Javier Chinen, Tram N. Cao, Eric A. Smith, Maria Soledad Caldirola, Liliana Bezrodnik, Saul Oswaldo Lugo Reyes, Francisco J. Espinosa Rosales, Nina Denisse Guerrero-Cursaru, Luis Alberto Pedroza, Cecilia M. Poli, Jose L. Franco, Claudia M. Trujillo Vargas, Juan Carlos Aldave Becerra, Nicola Wright, Thomas B. Issekutz, Andrew C. Issekutz, Jordan Abbott, Jason W. Caldwell, Diana K. Bayer, Alice Y. Chan, Alessandro Aiuti, Caterina Cancrini, Eva Holmberg, Christina West, Magnus Burstedt, Ender Karaca, Gözde Yesil, Hasibe Artac, Yavuz Bayram, Mehmed Musa Atik, Mohammad K. Eldomery, Mohammad S. Ehlayel, Stephen Jolles, Berit Flatø, Alison A. Bertuch, I. Celine Hanson, Victor W. Zhang, Lee Jun Wong, Jianhong Hu, Magdalena Walkiewicz, Yaping Yang, Christine M. Eng, Eric Boerwinkle, Richard A. Gibbs, William T. Shearer, Robert Lyle, Jordan S. Orange, James R. Lupski

Research output: Contribution to journalArticlepeer-review

213 Scopus citations


Background Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

Original languageEnglish
Pages (from-to)232-245
Number of pages14
JournalJournal of Allergy and Clinical Immunology
Issue number1
StatePublished - 1 Jan 2017
Externally publishedYes


  • Primary immunodeficiency disease
  • copy number variants
  • whole-exome sequencing


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