New human combined immunodeficiency caused by interferon regulatory factor 4 (IRF4) deficiency inherited by uniparental isodisomy

• Published in: Journal of allergy and clinical immunology 2018-05, Vol.141 (5), p.1924-1927.e18
• Main Authors: Bravo García-Morato, María, Aracil Santos, Francisco Javier, Briones, Alejandro Contreras, Blázquez Moreno, Alfonso, del Pozo Maté, Ángela, Domínguez-Soto, Ángeles, Beato Merino, María José, del Pino Molina, Lucía, Torres Canizales, Juan, Marin, Ana Victoria, Vallespín García, Elena, Feito Rodríguez, Marta, Plaza López Sabando, Diego, Jiménez-Reinoso, Anaïs, Mozo del Castillo, Yasmina, Sanz Santaeufemia, Francisco José, de Lucas-Laguna, Raúl, Cárdenas, Paula P., Casamayor Polo, Laura, Coronel Díaz, María, Valés-Gómez, Mar, Roldán Santiago, Ernesto, Ferreira Cerdán, Antonio, Nevado Blanco, Julián, Corbí, Ángel L., Reyburn, Hugh T., Regueiro, José Ramón, López-Granados, Eduardo, Rodríguez Pena, Rebeca
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Chromosomes; Dendritic cells; Female; Flow cytometry; Genes; Genotype & phenotype; Humans; Immunodeficiency; Immunologic Deficiency Syndromes - immunology; Infant; Interferon; Interferon regulatory factor; Interferon regulatory factor 4; Interferon Regulatory Factors - immunology; Lymphatic system; Lymphocytes; Mice; Mutation; Stem cells; Uniparental Disomy - immunology
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2017.12.995

Genetic analysis using a next-generation sequencing (NGS)–customized panel allowed us to exclude mutations in all previously reported PID-related genes. Because of the complexity of the clinical manifestations, a single nucleotide polymorphism (SNP) array was performed with DNA from the patient and her parents. At the age of 20 months, after PID confirmation, allogeneic hematopoietic stem cell transplantation was proposed to control infectious risk, eosinophilic/lymphocytic tissue damage, and lymphoproliferation. Because of the lack of a matched related or unrelated donor, which was unanticipated given the chromosome 6 homozygosity that affected the HLA loci, a haploidentical donor was considered. [...]Treg cells were in the low-to-normal range (see Table E3). Because of the uncertain long-term immunologic and clinical consequences of this novel mutation in heterozygous individuals, the maternal grandfather was considered a more suitable haploidentical donor in this complex clinical situation. According to best practices proposed by GATK, indel realignment was done to determine suspicious intervals likely to need realignment (GATK RealignerTargetCreator function), followed by local realignment of reads to correct misalignments caused by indels (GATK IndelRealigner function).