Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies.
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.
['Arts|Peer|P|', 'Simons|Annet|A|', 'AlZahrani|Mofareh S|MS|', 'Yilmaz|Elanur|E|', 'AlIdrissi|Eman|E|', 'van Aerde|Koen J|KJ|', 'Alenezi|Njood|N|', 'AlGhamdi|Hamza A|HA|', 'AlJubab|Hadeel A|HA|', 'Al-Hussaini|Abdulrahman A|AA|', 'AlManjomi|Fahad|F|', 'Alsaad|Alaa B|AB|', 'Alsaleem|Badr|B|', 'Andijani|Abdulrahman A|AA|', 'Asery|Ali|A|', 'Ballourah|Walid|W|', 'Bleeker-Rovers|Chantal P|CP|', 'van Deuren|Marcel|M|', 'van der Flier|Michiel|M|', 'Gerkes|Erica H|EH|', 'Gilissen|Christian|C|', 'Habazi|Murad K|MK|', 'Hehir-Kwa|Jayne Y|JY|', 'Henriet|Stefanie S|SS|', 'Hoppenreijs|Esther P|EP|', 'Hortillosa|Sarah|S|', 'Kerkhofs|Chantal H|CH|', 'Keski-Filppula|Riikka|R|', 'Lelieveld|Stefan H|SH|', 'Lone|Khurram|K|', 'MacKenzie|Marius A|MA|', 'Mensenkamp|Arjen R|AR|', 'Moilanen|Jukka|J|', 'Nelen|Marcel|M|', 'Ten Oever|Jaap|J|', 'Potjewijd|Judith|J|', 'van Paassen|Pieter|P|', 'Schuurs-Hoeijmakers|Janneke H M|JHM|', 'Simon|Anna|A|', 'Stokowy|Tomasz|T|', 'van de Vorst|Maartje|M|', 'Vreeburg|Maaike|M|', 'Wagner|Anja|A|', 'van Well|Gijs T J|GTJ|', 'Zafeiropoulou|Dimitra|D|', 'Zonneveld-Huijssoon|Evelien|E|', 'Veltman|Joris A|JA|', 'van Zelst-Stams|Wendy A G|WAG|', 'Faqeih|Eissa A|EA|', 'van de Veerdonk|Frank L|FL|', 'Netea|Mihai G|MG|', 'Hoischen|Alexander|A|']
D000293:Adolescent D000328:Adult D002675:Child, Preschool D005260:Female D005820:Genetic Testing D006801:Humans D007223:Infant D008297:Male D008875:Middle Aged D000081207:Primary Immunodeficiency Diseases D012680:Sensitivity and Specificity D000073359:Whole Exome Sequencing
Exome sequencing Routine diagnostics Primary immunodeficiencies Genetic diagnosis