Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

ABSTRACT: Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes. Keywords: Primary immunodeficiency disease; copy number variants; whole-exome sequencing.

• Autores: Franco Restrepo, José Luis; Trujillo Vargas, Claudia Milena; Aldave Becerra, Juan Carlos; Espinosa Rosales, Francisco J.; Pedroza, Luis Alberto; Caldirola, Maria Soledad; Lugo Reyes, Saul Oswaldo; Guerrero-Cursaru, Nina Denisse; Cancrini, Caterina; Hjorth-Hansen, Henrik
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2017
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/43122
• Acceso en línea: https://hdl.handle.net/10495/43122
• Palabra clave: DNA Copy Number Variations; Variaciones en el Número de Copia de ADN; Genomics; Genómica; High-Throughput Nucleotide Sequencing; Secuenciación de Nucleótidos de Alto Rendimiento; Immunologic Deficiency Syndromes; Síndromes de Inmunodeficiencia; https://id.nlm.nih.gov/mesh/D056915; https://id.nlm.nih.gov/mesh/D023281; https://id.nlm.nih.gov/mesh/D059014; https://id.nlm.nih.gov/mesh/D007153
• Rights: openAccess
• License: http://creativecommons.org/licenses/by-nc-nd/2.5/co/