Improving the diagnostic efficiency of primary immunodeficiencies with targeted next-generation sequencing

Fusaro, Mathieu; Rosain, Jérémie; Grandin, Virginie; Lambert, Nathalie; Hanein, Sylvain; Fourrage, Cécile; Renaud, Nicholas; Gil, Marine; Chevalier, Samuel; Chahla, Wadih Abou; Bader‐Meunier, Brigitte; Barlogis, Vincent; Blanche, Stéphane; Boutboul, David; Castelle, Martin; Comont, T.; Diana, Jean-Sébastien; Fieschi, Claire; Galicier, Lionel; Hermine, Olivier; Lefèvre‐Utile, Alain; Malphettes, Marion; Merlin, Étienne; Oksenhendler, Éric; Pasquet, Marlène; Suarez, Félipe; André-Schmutz, Isabelle; Béziat, Vivien; Basile, Geneviève de Saint; Villartay, Jean‐Pierre de; Kracker, Sven; Lagresle-Peyrou, Chantal; Latour, Sylvain; Rieux-Laucat, Frédéric; Mahlaoui, Nizar; Bole, Christine; Nitschké, Patrick; Hulier-Ammar, Elisabeth; Fischer, Alain; Moshous, Despina; Neven, Bénédicte; Alcaïs, Alexandre; Vogt, Guillaume; Bustamante, Jacinta; Pïcard, Capucine

doi:10.1016/j.jaci.2020.05.046

Cited by 22 publications

(10 citation statements)

References 9 publications

(11 reference statements)

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“…If we consider all possible and definite cases, the diagnostic yield for this cohort goes up to 24.74%, which is within the range of what other studies have reported (10 to 70%) on different cohorts of IEI patients employing various NGS approaches (Supplementary Table 3) (8,11,57,(73)(74)(75)(76)(77). The rates of positive hits between studies varies greatly based on the method used (WES or TGP), patient pre-selection and population, percentage of consanguinity, the number of selected genes, and filtering strategies.…”

Section: Discussionsupporting

confidence: 80%

Establishing the Molecular Diagnoses in a Cohort of 291 Patients With Predominantly Antibody Deficiency by Targeted Next-Generation Sequencing: Experience From a Monocentric Study

et al. 2021

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Predominantly antibody deficiencies (PAD) are a heterogeneous group of disorders characterized by dysfunctional antibody production, low immunoglobulin levels in serum and impaired vaccine responses. The clinical picture is variable, ranging from mild symptoms to severe complications, which may include autoimmunity, gastrointestinal disease, allergy, and malignancies. If left untreated, PAD patients are at risk of enduring disease progression, irreversible organ damage, and reduced life expectancy. A timely diagnosis has been shown to significantly improve disease prognosis. Here, we report on our experience using targeted gene panel sequencing by employing Agilent’s HaloPlex or SureSelect and Illumina’s MiSeq technologies in a cohort of 291 individuals who presented with low or absent immunoglobulin levels in combination with or without other clinical features. In total, we have detected over 57 novel or previously reported relevant mutations in ADA, ADA2, BTK, CTLA4, LRBA, NFKB1, NFKB2, PIK3CD, STAT3, and TNFRSF13B. Overall, a genetic diagnosis could be made in 24.7% of the investigated patients. The percentage of coverage for the targeted regions ranged from 90% to 98% in this study. Moreover, functional assays were performed on a defined group of the patients carrying candidate variants in CTLA4, LRBA, NFKB1 and BTK, which confirmed their deleterious effect on protein expression and/or function. This study reiterates that the immunological heterogeneity of predominantly antibody deficiencies may have a diverse genetic origin, although certain clinical features may hint towards a specific group of defects. Employing targeted sequencing panels proves to be a very time- and cost-efficient, yet reliable, method for the establishment of a genetic diagnosis in individuals with PAD. However, in case of negative panel results, or if functional testing reveals inconspicuous observations in patients with a clear indication for genetic testing, further work-up including whole exome or whole genome sequencing should be considered.

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Section: Discussionsupporting

confidence: 80%

Establishing the Molecular Diagnoses in a Cohort of 291 Patients With Predominantly Antibody Deficiency by Targeted Next-Generation Sequencing: Experience From a Monocentric Study

et al. 2021

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“…In the Italian SCID cohort, for example, genetically defined thymic disorders were found in 6% of the patients ( 121 ). This is almost certainly an underestimation of athymic cases, as a significant number of patients with inborn errors of immunity, including SCID, do not have a genetic diagnosis despite the expanding access to next-generation sequencing (NGS) ( 122 , 123 ). In a recent cohort of SCID patients, 7% of the patients did not have a genetic variant in any of the known SCID genes ( 124 ).…”

Section: Abnormalities Of Thymic Stromal Development and Functionmentioning

confidence: 99%

Current and Future Therapeutic Approaches for Thymic Stromal Cell Defects

2021

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Inborn errors of thymic stromal cell development and function lead to impaired T-cell development resulting in a susceptibility to opportunistic infections and autoimmunity. In their most severe form, congenital athymia, these disorders are life-threatening if left untreated. Athymia is rare and is typically associated with complete DiGeorge syndrome, which has multiple genetic and environmental etiologies. It is also found in rare cases of T-cell lymphopenia due to Nude SCID and Otofaciocervical Syndrome type 2, or in the context of genetically undefined defects. This group of disorders cannot be corrected by hematopoietic stem cell transplantation, but upon timely recognition as thymic defects, can successfully be treated by thymus transplantation using cultured postnatal thymic tissue with the generation of naïve T-cells showing a diverse repertoire. Mortality after this treatment usually occurs before immune reconstitution and is mainly associated with infections most often acquired pre-transplantation. In this review, we will discuss the current approaches to the diagnosis and management of thymic stromal cell defects, in particular those resulting in athymia. We will discuss the impact of the expanding implementation of newborn screening for T-cell lymphopenia, in combination with next generation sequencing, as well as the role of novel diagnostic tools distinguishing between hematopoietic and thymic stromal cell defects in facilitating the early consideration for thymus transplantation of an increasing number of patients and disorders. Immune reconstitution after the current treatment is usually incomplete with relatively common inflammatory and autoimmune complications, emphasizing the importance for improving strategies for thymus replacement therapy by optimizing the current use of postnatal thymus tissue and developing new approaches using engineered thymus tissue.

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“…Many PID genes can be evaluated with a single test and current broad based NGS PID panels include >300 genes. Depth of coverage is often excellent and exonic deletions, which commonly occur in several PIDs, are successfully detected (21). If a genetic etiology is not identified despite targeted NGS testing, whole exome sequencing (WES) or whole genome sequencing (WGS) can be considered for second-line genetic testing.…”

Section: How To Evaluatementioning

confidence: 99%

Primary Immunodeficiencies and Hematologic Malignancies: A Diagnostic Approach

et al. 2022

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An 18-month-old boy presented with stridor and cyanosis with crying. Chest x-ray revealed an anterior mediastinal mass. Prior history was remarkable for rotavirus gastroenteritis requiring admission for 5 weeks following his second rotavirus vaccination, and two episodes of otitis media. Growth and development were normal. Parents were first cousins, and family history was notable for a cousin with leukemia at age 2.

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Improving the diagnostic efficiency of primary immunodeficiencies with targeted next-generation sequencing

Cited by 22 publications

References 9 publications

Establishing the Molecular Diagnoses in a Cohort of 291 Patients With Predominantly Antibody Deficiency by Targeted Next-Generation Sequencing: Experience From a Monocentric Study

Establishing the Molecular Diagnoses in a Cohort of 291 Patients With Predominantly Antibody Deficiency by Targeted Next-Generation Sequencing: Experience From a Monocentric Study

Current and Future Therapeutic Approaches for Thymic Stromal Cell Defects

Primary Immunodeficiencies and Hematologic Malignancies: A Diagnostic Approach

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