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

• Published in: Genome medicine Vol. 11; no. 1; pp. 38 - 15
• Main Authors: Arts, Peer, Simons, Annet, AlZahrani, Mofareh S, Yilmaz, Elanur, AlIdrissi, Eman, van Aerde, Koen J, Alenezi, Njood, AlGhamdi, Hamza A, AlJubab, Hadeel A, Al-Hussaini, Abdulrahman A, AlManjomi, Fahad, Alsaad, Alaa B, Alsaleem, Badr, Andijani, Abdulrahman A, Asery, Ali, Ballourah, Walid, Bleeker-Rovers, Chantal P, van Deuren, Marcel, van der Flier, Michiel, Gerkes, Erica H, Gilissen, Christian, Habazi, Murad K, Hehir-Kwa, Jayne Y, Henriet, Stefanie S, Hoppenreijs, Esther P, Hortillosa, Sarah, Kerkhofs, Chantal H, Keski-Filppula, Riikka, Lelieveld, Stefan H, Lone, Khurram, MacKenzie, Marius A, Mensenkamp, Arjen R, Moilanen, Jukka, Nelen, Marcel, Ten Oever, Jaap, Potjewijd, Judith, van Paassen, Pieter, Schuurs-Hoeijmakers, Janneke H M, Simon, Anna, Stokowy, Tomasz, van de Vorst, Maartje, Vreeburg, Maaike, Wagner, Anja, van Well, Gijs T J, Zafeiropoulou, Dimitra, Zonneveld-Huijssoon, Evelien, Veltman, Joris A, van Zelst-Stams, Wendy A G, Faqeih, Eissa A, van de Veerdonk, Frank L, Netea, Mihai G, Hoischen, Alexander
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 17.06.2019; BioMed Central; BMC
• Subjects: Adolescent; Adult; Antibodies; Child, Preschool; Diagnosis; Disease; Exome sequencing; Exome Sequencing - methods; Exome Sequencing - standards; Female; Generic drugs; Genes; Genetic diagnosis; Genetic screening; Genetic testing; Genetic Testing - methods; Genetic Testing - standards; Genomes; Genomics; Humans; Immunodeficiency; Immunology; Infant; Infection; Infections; Male; Medical research; Medical tests; Middle Aged; Mutation; Novels; Patients; Population; Primary immunodeficiencies; Primary Immunodeficiency Diseases - diagnosis; Primary Immunodeficiency Diseases - genetics; Proteins; Routine diagnostics; Sensitivity and Specificity; Stem cells; Transplants & implants; United States > US; Europe; Primary immunodeficiencies; Exome sequencing; Genetic diagnosis; Routine diagnostics
• ISSN: 1756-994X; 1756-994X
• DOI: 10.1186/s13073-019-0649-3

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.