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

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    Abstract

    BackgroundDiagnosis 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.MethodsIn 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.ResultsFor 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%).ConclusionExome 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.

    Original languageEnglish
    Article number38
    Number of pages15
    JournalGenome medicine
    Volume11
    DOIs
    Publication statusPublished - 17-Jun-2019

    Keywords

    • Routine diagnostics
    • Genetic diagnosis
    • Exome sequencing
    • Primary immunodeficiencies
    • STEM-CELL TRANSPLANTATION
    • GAIN-OF-FUNCTION
    • HEMATOPOIETIC STEM
    • CENTROMERIC INSTABILITY
    • AUTOSOMAL-DOMINANT
    • MUTATIONS
    • DEFICIENCY
    • DISEASE
    • CHILDREN
    • VARIANTS
    • Additional file 4: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

      Habazi, M. K. (Contributor), Ballourah, W. (Contributor), Alenezi, N. (Contributor), Gerkes, E. (Contributor), Hehir-Kwa, J. Y. (Contributor), Veltman, J. A. (Contributor), Gilissen, C. (Contributor), MacKenzie, M. A. (Contributor), Van Zelst-Stams, W. A. G. (Contributor), Van Deuren, M. (Contributor), Schuurs-Hoeijmakers, J. H. M. (Contributor), Alidrissi, E. (Contributor), Netea, M. G. (Contributor), Wagner, A. (Contributor), Hortillosa, S. (Contributor), Alsaleem, B. (Contributor), Andijani, A. A. (Contributor), Keski-Filppula, R. (Contributor), Van Aerde, K. J. (Contributor), Kerkhofs, C. H. (Contributor), Asery, A. (Contributor), Nelen, M. (Contributor), Alsaad, A. B. (Contributor), Simon, A. (Contributor), Al-Hussaini, A. A. (Contributor), Aljubab, H. A. (Contributor), Van De Veerdonk, F. L. (Contributor), Vreeburg, M. (Contributor), Faqeih, E. A. (Contributor), Almanjomi, F. (Contributor), Lone, K. (Contributor), Zonneveld-Huijssoon, E. (Contributor), Van Der Flier, M. (Contributor), Simons, A. (Contributor), Van Well, G. T. J. (Contributor), Ten Oever, J. (Contributor), Arts, P. (Contributor), Stokowy, T. (Contributor), Van Paassen, P. (Contributor), Mensenkamp, A. R. (Contributor), Van De Vorst, M. (Contributor), Moilanen, J. (Contributor), Zafeiropoulou, D. (Contributor), Bleeker-Rovers, C. P. (Contributor), Hoppenreijs, E. P. (Contributor), Lelieveld, S. H. (Contributor), Alghamdi, H. A. (Contributor), Hoischen, A. (Contributor), Potjewijd, J. (Contributor), Yilmaz, E. (Contributor), Henriet, S. S. (Contributor) & Alzahrani, M. S. (Contributor), University of Groningen, 17-Jun-2019

      Dataset

    • Additional file 3: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

      Kerkhofs, C. H. (Contributor), Keski-Filppula, R. (Contributor), Van Zelst-Stams, W. A. G. (Contributor), Hehir-Kwa, J. Y. (Contributor), Alsaad, A. B. (Contributor), Mensenkamp, A. R. (Contributor), Hoischen, A. (Contributor), Moilanen, J. (Contributor), Hortillosa, S. (Contributor), Zonneveld-Huijssoon, E. (Contributor), Van Deuren, M. (Contributor), Henriet, S. S. (Contributor), Bleeker-Rovers, C. P. (Contributor), Gilissen, C. (Contributor), Stokowy, T. (Contributor), Hoppenreijs, E. P. (Contributor), Alzahrani, M. S. (Contributor), Veltman, J. A. (Contributor), Faqeih, E. A. (Contributor), Lelieveld, S. H. (Contributor), Van Der Flier, M. (Contributor), Van Paassen, P. (Contributor), Alenezi, N. (Contributor), Schuurs-Hoeijmakers, J. H. M. (Contributor), Netea, M. G. (Contributor), Van Well, G. T. J. (Contributor), Gerkes, E. (Contributor), Vreeburg, M. (Contributor), Al-Hussaini, A. A. (Contributor), Almanjomi, F. (Contributor), Habazi, M. K. (Contributor), Ten Oever, J. (Contributor), Andijani, A. A. (Contributor), Ballourah, W. (Contributor), Lone, K. (Contributor), Aljubab, H. A. (Contributor), Arts, P. (Contributor), Simons, A. (Contributor), Alsaleem, B. (Contributor), MacKenzie, M. A. (Contributor), Alghamdi, H. A. (Contributor), Wagner, A. (Contributor), Van De Veerdonk, F. L. (Contributor), Potjewijd, J. (Contributor), Nelen, M. (Contributor), Zafeiropoulou, D. (Contributor), Van Aerde, K. J. (Contributor), Asery, A. (Contributor), Van De Vorst, M. (Contributor), Alidrissi, E. (Contributor), Yilmaz, E. (Contributor) & Simon, A. (Contributor), University of Groningen, 17-Jun-2019

      Dataset

    • Additional file 5: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

      Zonneveld-Huijssoon, E. (Contributor), Alsaleem, B. (Contributor), Van Deuren, M. (Contributor), Kerkhofs, C. H. (Contributor), Hoppenreijs, E. P. (Contributor), Al-Hussaini, A. A. (Contributor), Simon, A. (Contributor), Alzahrani, M. S. (Contributor), Alidrissi, E. (Contributor), Hoischen, A. (Contributor), Stokowy, T. (Contributor), Ballourah, W. (Contributor), Mensenkamp, A. R. (Contributor), Henriet, S. S. (Contributor), Gilissen, C. (Contributor), Andijani, A. A. (Contributor), Lone, K. (Contributor), Van Well, G. T. J. (Contributor), Hehir-Kwa, J. Y. (Contributor), Alghamdi, H. A. (Contributor), Ten Oever, J. (Contributor), Habazi, M. K. (Contributor), Moilanen, J. (Contributor), Wagner, A. (Contributor), Yilmaz, E. (Contributor), MacKenzie, M. A. (Contributor), Van Aerde, K. J. (Contributor), Lelieveld, S. H. (Contributor), Van De Veerdonk, F. L. (Contributor), Almanjomi, F. (Contributor), Faqeih, E. A. (Contributor), Aljubab, H. A. (Contributor), Alsaad, A. B. (Contributor), Bleeker-Rovers, C. P. (Contributor), Potjewijd, J. (Contributor), Schuurs-Hoeijmakers, J. H. M. (Contributor), Simons, A. (Contributor), Veltman, J. A. (Contributor), Gerkes, E. (Contributor), Hortillosa, S. (Contributor), Van De Vorst, M. (Contributor), Van Zelst-Stams, W. A. G. (Contributor), Arts, P. (Contributor), Nelen, M. (Contributor), Zafeiropoulou, D. (Contributor), Vreeburg, M. (Contributor), Asery, A. (Contributor), Van Der Flier, M. (Contributor), Keski-Filppula, R. (Contributor), Van Paassen, P. (Contributor), Alenezi, N. (Contributor) & Netea, M. G. (Contributor), University of Groningen, 17-Jun-2019

      Dataset

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