Expanding the Clinical and Genetic Spectra of Primary Immunodeficiency-Related Disorders With Clinical Exome Sequencing : Expected and Unexpected Findings
Rudilla, Francesc (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Franco-Jarava, Clara (Jeffrey Model Foundation Excellence Center)
Martínez Gallo, Mónica (Jeffrey Model Foundation Excellence Center)
Garcia-Prat, Marina (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Martín-Nalda, Andrea (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Rivière, Jacques (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Aguiló-Cucurull, Aina (Jeffrey Model Foundation Excellence Center)
Mongay, Laura (Banc de Sang i Teixits)
Vidal, Francisco (Instituto de Salud Carlos III)
Solanich, Xavier (Hospital Universitari de Bellvitge)
Irastorza, Iñaki (Hospital Universitario de Cruces (Barakaldo, País Basc))
Santos-Pérez, Juan Luis (Hospital Universitario Virgen de las Nieves (Granada))
Tercedor Sánchez, Jesús (Hospital Universitario Virgen de las Nieves (Granada))
Cusco, Ivon (Hospital Universitari Vall d'Hebron)
Serra, Clara (Hospital Universitari Vall d'Hebron)
Baz-Redón, Noelia (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Fernández Cancio, Mónica (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Carreras, Carmen (Hospital Universitari i Politècnic La Fe (València))
Vagace, Manuel (Complejo Hospitalario Universitario de Badajoz)
García-Patos Briones, Vicente (Hospital Universitari Vall d'Hebron)
Pujol-Borrell, Ricardo (Jeffrey Model Foundation Excellence Center)
Soler-Palacín, Pere (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Colobrán Oriol, Roger (Hospital Universitari Vall d'Hebron)
Universitat Autònoma de Barcelona

Data:	2019
Resum:	Primary immunodeficiencies (PIDs) refer to a clinically, immunologically, and genetically heterogeneous group of over 350 disorders affecting development or function of the immune system. The increasing use of next-generation sequencing (NGS) technology has greatly facilitated identification of genetic defects in PID patients in daily clinical practice. Several NGS approaches are available, from the unbiased whole exome sequencing (WES) to specific gene panels. Here, we report on a 3-year experience with clinical exome sequencing (CES) for genetic diagnosis of PIDs. We used the TruSight One sequencing panel, which includes 4,813 disease-associated genes, in 61 unrelated patients (pediatric and adults). The analysis was done in 2 steps: first, we focused on a virtual PID panel and then, we expanded the analysis to the remaining genes. A molecular diagnosis was achieved in 19 (31%) patients: 12 (20%) with mutations in genes included in the virtual PID panel and 7 (11%) with mutations in other genes. These latter cases provided interesting and somewhat unexpected findings that expand the clinical and genetic spectra of PID-related disorders, and are useful to consider in the differential diagnosis. We also discuss 5 patients (8%) with incomplete genotypes or variants of uncertain significance. Finally, we address the limitations of CES exemplified by 7 patients (11%) with negative results on CES who were later diagnosed by other approaches (more specific PID panels, WES, and comparative genomic hybridization array). In summary, the genetic diagnosis rate using CES was 31% (including a description of 12 novel mutations), which rose to 42% after including diagnoses achieved by later use of other techniques. The description of patients with mutations in genes not included in the PID classification illustrates the heterogeneity and complexity of PID-related disorders.
Ajuts:	Instituto de Salud Carlos III PI14-00405 Instituto de Salud Carlos III PI17-00660
Nota:	We are deeply grateful to the affected individuals who participated in this study and their families. We thank the Barcelona PID Foundation for patient support and for funding MG-P. We acknowledge Celine Cavallo for English language support. Funding. This study was funded by Instituto de Salud Carlos III, grants PI14/00405 and PI17/00660, cofinanced by the European Regional Development Fund (ERDF).
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Primary immunodeficiencies ; Next generation sequencing ; Clinical exome sequencing ; TruSight one ; Sequencing panel ; Mutations ; Genetic variants
Publicat a:	Frontiers in immunology, Vol. 10 (january 2019) , p. 2325, ISSN 1664-3224

DOI: 10.3389/fimmu.2019.02325
PMID: 31681265

0 p, 658.9 KB

El registre apareix a les col·leccions:
Articles > Articles de recerca
Articles > Articles publicats