University of Oulu

Arts, P., Simons, A., AlZahrani, M.S. et al. Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies. Genome Med 11, 38 (2019).

Exome sequencing in routine diagnostics : a generic test for 254 patients with primary immunodeficiencies

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Author: Arts, Peer1,2,3; Simons, Annet1; AlZahrani, Mofareh S.4;
Organizations: 1Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.
2SA Pathol, Ctr Canc Biol, Dept Genet & Mol Pathol, Adelaide, SA, Australia.
3Univ South Australia, Adelaide, SA, Australia.
4Childrens Specialist Hosp, King Fahad Med City, Dept Pediat, Riyadh, Saudi Arabia.
5Akdeniz Univ, Dept Med Biol, Fac Med, Antalya, Turkey.
6Radboud Univ Nijmegen, Med Ctr, Dept Pediat Immunol, Pediat, Nijmegen, Netherlands.
7King Fahad Med City, Comprehens Canc Ctr, Dept Pediat Hematol & Oncol, Riyadh, Saudi Arabia.
8Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, Radboud Expertise Ctr Immunodeficiency & Autoinf, Nijmegen, Netherlands.
9Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Dept Pediat Infect Dis & Immunol, Utrecht, Netherlands.
10Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.
11Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands.
12Radboud Univ Nijmegen, Med Ctr, Dept Pediat Rheumatol, Pediat, Nijmegen, Netherlands.
13Maastricht Univ, Med Ctr, Dept Clin Genet, Maastricht, Netherlands.
14Univ Oulu, PEDEGO Res Unit, Oulu, Finland.
15Univ Oulu, Med Res Ctr Oulu, Oulu, Finland.
16Oulu Univ Hosp, Dept Clin Genet, Oulu, Finland.
17Radboud Univ Nijmegen, Med Ctr, Dept Hematol, Nijmegen, Netherlands.
18Maastricht Univ, Med Ctr, Dept Clin Immunol, Maastricht, Netherlands.
19Univ Bergen, Computat Biol Unit, Dept Informat, Dept Clin Sci, N-5020 Bergen, Norway.
20Univ Med Ctr, Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands.
21Maastricht Univ, Med Ctr, Sch Nutr & Translat Res Metab NUTRIM, Dept Pediat, Maastricht, Netherlands.
22Newcastle Univ, Inst Genet Med, Newcastle Upon Tyne, Tyne & Wear, England.
23Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, POB 9101, NL-6500 HB Nijmegen, Netherlands.
24Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, POB 9101, NL-6500 HB Nijmegen, Netherlands.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.3 MB)
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Language: English
Published: Springer Nature, 2019
Publish Date: 2020-04-28


Background: Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management of the disease. Exome sequencing may provide a genetic diagnosis in a significant number of patients in a single genetic test.

Methods: In May 2013, we implemented exome sequencing in routine diagnostics for patients suffering from PIDs. This study reports the clinical utility and diagnostic yield for a heterogeneous group of 254 consecutively referred PID patients from 249 families. For the majority of patients, the clinical diagnosis was based on clinical criteria including rare and/or unusual severe bacterial, viral, or fungal infections, sometimes accompanied by autoimmune manifestations. Functional immune defects were interpreted in the context of aberrant immune cell populations, aberrant antibody levels, or combinations of these factors.

Results: For 62 patients (24%), exome sequencing identified pathogenic variants in well-established PID genes. An exome-wide analysis diagnosed 10 additional patients (4%), providing diagnoses for 72 patients (28%) from 68 families altogether. The genetic diagnosis directly indicated novel treatment options for 25 patients that received a diagnosis (34%).

Conclusion: Exome sequencing as a first-tier test for PIDs granted a diagnosis for 28% of patients. Importantly, molecularly defined diagnoses indicated altered therapeutic options in 34% of cases. In addition, exome sequencing harbors advantages over gene panels as a truly generic test for all genetic diseases, including in silico extension of existing gene lists and re-analysis of existing data.

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Series: Genome medicine
ISSN: 1756-994X
ISSN-E: 1756-994X
ISSN-L: 1756-994X
Volume: 11
Article number: 38
DOI: 10.1186/s13073-019-0649-3
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: AH was supported by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. MGN was supported by the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Spinoza grant) and the European Research Council (grant agreement No 310372). JAV was supported by Nederlandse Organisatie voor Wetenschappelijk Onderzoek (918-15-667).
Copyright information: © The Author(s). 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.