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

ABSTRACT: 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.

SUBMITTER: Arts P

PROVIDER: S-EPMC6572765 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

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

Genome medicine 20190617 1

<h4>Background</h4>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.<h4>Methods</h4>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 p ...[more]

PMID: 31203817

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Project description:BackgroundRecently, a growing number of novel genetic defects underlying primary immunodeficiencies (PIDs) have been identified, increasing the number of PID up to more than 250 well-defined forms. Next-generation sequencing (NGS) technologies and proper filtering strategies greatly contributed to this rapid evolution, providing the possibility to rapidly and simultaneously analyze large numbers of genes or the whole exome.ObjectiveTo evaluate the role of targeted NGS and whole exome sequencing (WES) in the diagnosis of a case series, characterized by complex or atypical clinical features suggesting a PID, difficult to diagnose using the current diagnostic procedures.MethodsWe retrospectively analyzed genetic variants identified through targeted NGS or WES in 45 patients with complex PID of unknown etiology.ResultsForty-seven variants were identified using targeted NGS, while 5 were identified using WES. Newly identified genetic variants were classified into four groups: (I) variations associated with a well-defined PID, (II) variations associated with atypical features of a well-defined PID, (III) functionally relevant variations potentially involved in the immunological features, and (IV) non-diagnostic genotype, in whom the link with phenotype is missing. We reached a conclusive genetic diagnosis in 7/45 patients (~16%). Among them, four patients presented with a typical well-defined PID. In the remaining three cases, mutations were associated with unexpected clinical features, expanding the phenotypic spectrum of typical PIDs. In addition, we identified 31 variants in 10 patients with complex phenotype, individually not causative per se of the disorder.ConclusionNGS technologies represent a cost-effective and rapid first-line genetic approach for the evaluation of complex PIDs. WES, despite a moderate higher cost compared to targeted, is emerging as a valuable tool to reach in a timely manner, a PID diagnosis with a considerable potential to draw genotype-phenotype correlation. Nevertheless, a large fraction of patients still remains without a conclusive diagnosis. In these patients, the sum of non-diagnostic variants might be proven informative in future studies with larger cohorts of patients.

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

Publications

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

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