Frontiers in Immunology (Oct 2019)

Expanding the Clinical and Genetic Spectra of Primary Immunodeficiency-Related Disorders With Clinical Exome Sequencing: Expected and Unexpected Findings

  • Francesc Rudilla,
  • Francesc Rudilla,
  • Clara Franco-Jarava,
  • Clara Franco-Jarava,
  • Mónica Martínez-Gallo,
  • Mónica Martínez-Gallo,
  • Marina Garcia-Prat,
  • Marina Garcia-Prat,
  • Andrea Martín-Nalda,
  • Andrea Martín-Nalda,
  • Jacques Rivière,
  • Jacques Rivière,
  • Aina Aguiló-Cucurull,
  • Aina Aguiló-Cucurull,
  • Laura Mongay,
  • Francisco Vidal,
  • Francisco Vidal,
  • Francisco Vidal,
  • Xavier Solanich,
  • Iñaki Irastorza,
  • Juan Luis Santos-Pérez,
  • Jesús Tercedor Sánchez,
  • Ivon Cuscó,
  • Clara Serra,
  • Noelia Baz-Redón,
  • Mónica Fernández-Cancio,
  • Mónica Fernández-Cancio,
  • Carmen Carreras,
  • José Manuel Vagace,
  • Vicenç Garcia-Patos,
  • Ricardo Pujol-Borrell,
  • Ricardo Pujol-Borrell,
  • Pere Soler-Palacín,
  • Pere Soler-Palacín,
  • Roger Colobran,
  • Roger Colobran,
  • Roger Colobran

DOI
https://doi.org/10.3389/fimmu.2019.02325
Journal volume & issue
Vol. 10

Abstract

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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.

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