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

Autor: Arts P; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia., Simons A; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., AlZahrani MS; Department of Pediatrics, Children's specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., Yilmaz E; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Medical Biology, Faculty of Medicine, Akdeniz University, Antalya, Turkey., AlIdrissi E; Department of Pediatrics, Children's specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., van Aerde KJ; Department of Pediatric immunology, Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands., Alenezi N; Department of Pediatrics, Children's specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., AlGhamdi HA; Department of Pediatrics, Children's specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., AlJubab HA; Department of Pediatrics, Children's specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., Al-Hussaini AA; Department of Pediatrics, Children's specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., AlManjomi F; Department of Pediatric Hematology and Oncology, Comprehensive Cancer center, King Fahad Medical City, Riyadh, Saudi Arabia., Alsaad AB; Department of Pediatrics, Children's specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., Alsaleem B; Department of Pediatrics, Children's specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., Andijani AA; Department of Pediatrics, Children's specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., Asery A; Department of Pediatrics, Children's specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., Ballourah W; Department of Pediatric Hematology and Oncology, Comprehensive Cancer center, King Fahad Medical City, Riyadh, Saudi Arabia., Bleeker-Rovers CP; Radboud Expertise Center for Immunodeficiency and Autoinflammation, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands., van Deuren M; Radboud Expertise Center for Immunodeficiency and Autoinflammation, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands., van der Flier M; Department of Pediatric immunology, Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Pediatric Infectious Diseases and Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands., Gerkes EH; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., Gilissen C; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Habazi MK; Department of Pediatrics, Children's specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., Hehir-Kwa JY; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Henriet SS; Department of Pediatric immunology, Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands., Hoppenreijs EP; Department of Pediatric Rheumatology, Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands., Hortillosa S; Department of Pediatrics, Children's specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., Kerkhofs CH; Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, The Netherlands., Keski-Filppula R; PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, Oulu, Finland.; Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland., Lelieveld SH; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Lone K; Department of Pediatrics, Children's specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., MacKenzie MA; Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands., Mensenkamp AR; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Moilanen J; PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, Oulu, Finland.; Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland., Nelen M; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Ten Oever J; Radboud Expertise Center for Immunodeficiency and Autoinflammation, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands., Potjewijd J; Department of Clinical Immunology, Maastricht University Medical Center, Maastricht, The Netherlands., van Paassen P; Department of Clinical Immunology, Maastricht University Medical Center, Maastricht, The Netherlands., Schuurs-Hoeijmakers JHM; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Simon A; Radboud Expertise Center for Immunodeficiency and Autoinflammation, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands., Stokowy T; Department of Clinical Science, Department of Informatics, Computational Biology Unit, University of Bergen, 5020, Bergen, Norway., van de Vorst M; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Vreeburg M; Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, The Netherlands., Wagner A; Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands., van Well GTJ; Department of Pediatrics, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center+, Maastricht University, Maastricht, The Netherlands., Zafeiropoulou D; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Zonneveld-Huijssoon E; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., Veltman JA; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.; Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK., van Zelst-Stams WAG; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Faqeih EA; Department of Pediatrics, Children's specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., van de Veerdonk FL; Radboud Expertise Center for Immunodeficiency and Autoinflammation, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands., Netea MG; Radboud Expertise Center for Immunodeficiency and Autoinflammation, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands., Hoischen A; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. alexander.hoischen@radboudumc.nl.; Radboud Expertise Center for Immunodeficiency and Autoinflammation, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. alexander.hoischen@radboudumc.nl.; Department of Human Genetics and Department of Internal Medicine, Radboud University Medical Center, P.O. Box 9101, 6500, HB, Nijmegen, The Netherlands. alexander.hoischen@radboudumc.nl.
Jazyk: angličtina
Zdroj: Genome medicine [Genome Med] 2019 Jun 17; Vol. 11 (1), pp. 38. Date of Electronic Publication: 2019 Jun 17.
DOI: 10.1186/s13073-019-0649-3
Abstrakt: 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.
Databáze: MEDLINE
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