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

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

doi:10.1186/s13073-019-0649-3

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

Journal article

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

Peer Arts, Annet Simons, Mofareh S AlZahrani, Elanur Yilmaz, Eman AlIdrissi, Koen J van Aerde, Njood Alenezi, Hamza A AlGhamdi, Hadeel A AlJubab, Abdulrahman A Al-Hussaini, …

Genome medicine, Vol.11(1), pp.38-38

17/06/2019

DOI: https://doi.org/10.1186/s13073-019-0649-3

PMCID: PMC6572765

PMID: 31203817

Abstract

Adolescent

Adult

Child, Preschool

Female

Genetic Testing - methods

Genetic Testing - standards

Humans

Infant

Male

Middle Aged

Primary Immunodeficiency Diseases - diagnosis

Primary Immunodeficiency Diseases - genetics

Sensitivity and Specificity

Whole Exome Sequencing - methods

Whole Exome Sequencing - standards

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. 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. 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%). 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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Title: Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies
Creators - without role: Peer Arts - Radboud University Nijmegen
Annet Simons - Radboud University Nijmegen
Mofareh S AlZahrani - Department of Pediatrics, Children’s specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Elanur Yilmaz - Radboud University Nijmegen
Eman AlIdrissi - Department of Pediatrics, Children’s specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Koen J van Aerde - Radboud University Nijmegen
Njood Alenezi - Department of Pediatrics, Children’s specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Hamza A AlGhamdi - Department of Pediatrics, Children’s specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Hadeel A AlJubab - Department of Pediatrics, Children’s specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Abdulrahman A Al-Hussaini - Department of Pediatrics, Children’s specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Fahad AlManjomi - King Fahd Medical City
Alaa B Alsaad - Department of Pediatrics, Children’s specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Badr Alsaleem - Department of Pediatrics, Children’s specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Abdulrahman A Andijani - Department of Pediatrics, Children’s specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Ali Asery - Department of Pediatrics, Children’s specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Walid Ballourah - King Fahd Medical City
Chantal P Bleeker-Rovers - Radboud University Nijmegen
Marcel van Deuren - Radboud University Nijmegen
Michiel van der Flier - Radboud University Nijmegen
Erica H Gerkes - University Medical Center Groningen
Christian Gilissen - Radboud University Nijmegen
Murad K Habazi - Department of Pediatrics, Children’s specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Jayne Y Hehir-Kwa - Radboud University Nijmegen
Stefanie S Henriet - Radboud University Nijmegen
Esther P Hoppenreijs - Department of Pediatric Rheumatology, Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands
Sarah Hortillosa - Department of Pediatrics, Children’s specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Chantal H Kerkhofs - Maastricht University
Riikka Keski-Filppula - University of Oulu
Stefan H Lelieveld - Radboud University Nijmegen
Khurram Lone - Department of Pediatrics, Children’s specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Marius A MacKenzie - Radboud University Nijmegen
Arjen R Mensenkamp - Radboud University Nijmegen
Jukka Moilanen - University of Oulu
Marcel Nelen - Radboud University Nijmegen
Jaap Ten Oever - Radboud Expertise Center for Immunodeficiency and Autoinflammation, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
Judith Potjewijd - Maastricht University
Pieter van Paassen - Maastricht University
Janneke H M Schuurs-Hoeijmakers - Radboud University Nijmegen
Anna Simon - Radboud University Nijmegen
Tomasz Stokowy - University of Bergen
Maartje van de Vorst - Radboud University Nijmegen
Maaike Vreeburg - Maastricht University
Anja Wagner - Erasmus MC
Gijs T J van Well - Maastricht University
Dimitra Zafeiropoulou - Radboud University Nijmegen
Evelien Zonneveld-Huijssoon - University Medical Center Groningen
Joris A Veltman - Radboud University Nijmegen
Wendy A G van Zelst-Stams - Radboud University Nijmegen
Eissa A Faqeih - Department of Pediatrics, Children’s specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Frank L van de Veerdonk - Radboud University Nijmegen
Mihai G Netea - Radboud University Nijmegen
Alexander Hoischen - Radboud University Nijmegen
Publication Details: Genome medicine, Vol.11(1), pp.38-38
Identifiers: 9913849408331
Academic Unit: Alfaisal University; King Saud University
Language: English
Resource Type: Journal article