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

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doi:10.1186/s13073-019-0649-3

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 language	English
Article number	38
Number of pages	15
Journal	Genome medicine
Volume	11
DOIs	https://doi.org/10.1186/s13073-019-0649-3
Publication status	Published - 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

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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
DOI: 10.6084/m9.figshare.8282177.v1, https://doi.org/10.6084%2Fm9.figshare.8282177.v1
Dataset
Additional file 6: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies
Moilanen, J. (Contributor), Veltman, J. A. (Contributor), Alenezi, N. (Contributor), Netea, M. G. (Contributor), Faqeih, E. A. (Contributor), Al-Hussaini, A. A. (Contributor), Yilmaz, E. (Contributor), Alzahrani, M. S. (Contributor), Potjewijd, J. (Contributor), Keski-Filppula, R. (Contributor), Mensenkamp, A. R. (Contributor), Lelieveld, S. H. (Contributor), Henriet, S. S. (Contributor), Hoppenreijs, E. P. (Contributor), Zafeiropoulou, D. (Contributor), Alsaad, A. B. (Contributor), Van Well, G. T. J. (Contributor), Almanjomi, F. (Contributor), Alidrissi, E. (Contributor), MacKenzie, M. A. (Contributor), Lone, K. (Contributor), Gilissen, C. (Contributor), Nelen, M. (Contributor), Simon, A. (Contributor), Alghamdi, H. A. (Contributor), Arts, P. (Contributor), Asery, A. (Contributor), Van Paassen, P. (Contributor), Ballourah, W. (Contributor), Wagner, A. (Contributor), Hortillosa, S. (Contributor), Hoischen, A. (Contributor), Hehir-Kwa, J. Y. (Contributor), Van De Vorst, M. (Contributor), Vreeburg, M. (Contributor), Aljubab, H. A. (Contributor), Simons, A. (Contributor), Stokowy, T. (Contributor), Zonneveld-Huijssoon, E. (Contributor), Habazi, M. K. (Contributor), Kerkhofs, C. H. (Contributor), Gerkes, E. (Contributor), Alsaleem, B. (Contributor), Ten Oever, J. (Contributor), Van Zelst-Stams, W. A. G. (Contributor), Van De Veerdonk, F. L. (Contributor), Van Aerde, K. J. (Contributor), Andijani, A. A. (Contributor), Van Deuren, M. (Contributor), Van Der Flier, M. (Contributor), Schuurs-Hoeijmakers, J. H. M. (Contributor) & Bleeker-Rovers, C. P. (Contributor), University of Groningen, 17-Jun-2019
DOI: 10.6084/m9.figshare.8282186.v1, https://doi.org/10.6084%2Fm9.figshare.8282186.v1
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
DOI: 10.6084/m9.figshare.8282183.v1, https://doi.org/10.6084%2Fm9.figshare.8282183.v1
Dataset

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@article{5008f454060e459ea1dacba20f7d032e,

title = "Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies",

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.",

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",

author = "Test and Peer Arts and Annet Simons and AlZahrani, {Mofareh S.} and Elanur Yilmaz and Eman AlIdrissi and {van Aerde}, {Koen J.} and Njood Alenezi and AlGhamdi, {Hamza A.} and AlJubab, {Hadeel A.} and Al-Hussaini, {Abdulrahman A.} and Fahad AlManjomi and Alsaad, {Alaa B.} and Badr Alsaleem and Andijani, {Abdulrahman A.} and Ali Asery and Walid Ballourah and Bleeker-Rovers, {Chantal P.} and {van Deuren}, Marcel and {van der Flier}, Michiel and Gerkes, {Erica H.} and Christian Gilissen and Habazi, {Murad K.} and Hehir-Kwa, {Jayne Y.} and Henriet, {Stefanie S.} and Hoppenreijs, {Esther P.} and Sarah Hortillosa and Kerkhofs, {Chantal H.} and Riikka Keski-Filppula and Lelieveld, {Stefan H.} and Khurram Lone and MacKenzie, {Marius A.} and Mensenkamp, {Arjen R.} and Jukka Moilanen and Marcel Nelen and {ten Oever}, Jaap and Judith Potjewijd and {van Paassen}, Pieter and Schuurs-Hoeijmakers, {Janneke H. M.} and Anna Simon and Tomasz Stokowy and {van de Vorst}, Maartje and Maaike Vreeburg and Anja Wagner and {van Well}, {Gijs T. J.} and Dimitra Zafeiropoulou and Evelien Zonneveld-Huijssoon and Veltman, {Joris A.} and {van Zelst-Stams}, {Wendy A. G.} and Faqeih, {Eissa A.} and {van de Veerdonk}, {Frank L.}",

year = "2019",

month = jun,

day = "17",

doi = "10.1186/s13073-019-0649-3",

language = "English",

volume = "11",

journal = "Genome medicine",

issn = "1756-994X",

publisher = "BMC",

}

TY - JOUR

T1 - Exome sequencing in routine diagnostics

T2 - a generic test for 254 patients with primary immunodeficiencies

AU - Test

AU - Arts, Peer

AU - Simons, Annet

AU - AlZahrani, Mofareh S.

AU - Yilmaz, Elanur

AU - AlIdrissi, Eman

AU - van Aerde, Koen J.

AU - Alenezi, Njood

AU - AlGhamdi, Hamza A.

AU - AlJubab, Hadeel A.

AU - Al-Hussaini, Abdulrahman A.

AU - AlManjomi, Fahad

AU - Alsaad, Alaa B.

AU - Alsaleem, Badr

AU - Andijani, Abdulrahman A.

AU - Asery, Ali

AU - Ballourah, Walid

AU - Bleeker-Rovers, Chantal P.

AU - van Deuren, Marcel

AU - van der Flier, Michiel

AU - Gerkes, Erica H.

AU - Gilissen, Christian

AU - Habazi, Murad K.

AU - Hehir-Kwa, Jayne Y.

AU - Henriet, Stefanie S.

AU - Hoppenreijs, Esther P.

AU - Hortillosa, Sarah

AU - Kerkhofs, Chantal H.

AU - Keski-Filppula, Riikka

AU - Lelieveld, Stefan H.

AU - Lone, Khurram

AU - MacKenzie, Marius A.

AU - Mensenkamp, Arjen R.

AU - Moilanen, Jukka

AU - Nelen, Marcel

AU - ten Oever, Jaap

AU - Potjewijd, Judith

AU - van Paassen, Pieter

AU - Schuurs-Hoeijmakers, Janneke H. M.

AU - Simon, Anna

AU - Stokowy, Tomasz

AU - van de Vorst, Maartje

AU - Vreeburg, Maaike

AU - Wagner, Anja

AU - van Well, Gijs T. J.

AU - Zafeiropoulou, Dimitra

AU - Zonneveld-Huijssoon, Evelien

AU - Veltman, Joris A.

AU - van Zelst-Stams, Wendy A. G.

AU - Faqeih, Eissa A.

AU - van de Veerdonk, Frank L.

PY - 2019/6/17

Y1 - 2019/6/17

N2 - 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.

AB - 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.

KW - Routine diagnostics

KW - Genetic diagnosis

KW - Exome sequencing

KW - Primary immunodeficiencies

KW - STEM-CELL TRANSPLANTATION

KW - GAIN-OF-FUNCTION

KW - HEMATOPOIETIC STEM

KW - CENTROMERIC INSTABILITY

KW - AUTOSOMAL-DOMINANT

KW - MUTATIONS

KW - DEFICIENCY

KW - DISEASE

KW - CHILDREN

KW - VARIANTS

U2 - 10.1186/s13073-019-0649-3

DO - 10.1186/s13073-019-0649-3

M3 - Article

SN - 1756-994X

VL - 11

JO - Genome medicine

JF - Genome medicine

M1 - 38

ER -

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

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

Additional file 6: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

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

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