Hyper-IgE Syndrome due to an Elusive Novel Intronic Homozygous Variant in DOCK8.

Autor:	Tangye SG; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, New South Wales, 2010, Australia.; St Vincent's Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia.; Clinical Immunogenomics Research Consortium of Australasia (CIRCA), Sydney, New South Wales, Australia., Gray PE; Clinical Immunogenomics Research Consortium of Australasia (CIRCA), Sydney, New South Wales, Australia.; Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Sydney, New South Wales, Australia.; School of Women's and Children's Health, UNSW Sydney, Sydney, New South Wales, Australia., Pillay BA; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, New South Wales, 2010, Australia.; St Vincent's Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia., Yap JY; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, New South Wales, 2010, Australia.; Clinical Immunogenomics Research Consortium of Australasia (CIRCA), Sydney, New South Wales, Australia., Figgett WA; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, New South Wales, 2010, Australia., Reeves J; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, New South Wales, 2010, Australia.; St Vincent's Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia., Kummerfeld SK; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, New South Wales, 2010, Australia., Stoddard J; Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, MD, USA., Uzel G; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Jing H; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Su HC; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Campbell DE; Department of Allergy and Immunology, Children's Hospital at Westmead, Westmead, New South Wales, Australia.; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia., Sullivan A; Clinical Immunogenomics Research Consortium of Australasia (CIRCA), Sydney, New South Wales, Australia.; Queensland Children's Hospital and University of Queensland, South Brisbane, Queensland, Australia., Burnett L; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, New South Wales, 2010, Australia.; St Vincent's Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia.; Clinical Immunogenomics Research Consortium of Australasia (CIRCA), Sydney, New South Wales, Australia.; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia., Peake J; Clinical Immunogenomics Research Consortium of Australasia (CIRCA), Sydney, New South Wales, Australia.; Queensland Children's Hospital and University of Queensland, South Brisbane, Queensland, Australia., Ma CS; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, New South Wales, 2010, Australia. c.ma@garvan.org.au.; St Vincent's Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia. c.ma@garvan.org.au.; Clinical Immunogenomics Research Consortium of Australasia (CIRCA), Sydney, New South Wales, Australia. c.ma@garvan.org.au.
Jazyk:	angličtina
Zdroj:	Journal of clinical immunology [J Clin Immunol] 2022 Jan; Vol. 42 (1), pp. 119-129. Date of Electronic Publication: 2021 Oct 17.
DOI:	10.1007/s10875-021-01152-x
Abstrakt:	Rare, biallelic loss-of-function mutations in DOCK8 result in a combined immune deficiency characterized by severe and recurrent cutaneous infections, eczema, allergies, and susceptibility to malignancy, as well as impaired humoral and cellular immunity and hyper-IgE. The advent of next-generation sequencing technologies has enabled the rapid molecular diagnosis of rare monogenic diseases, including inborn errors of immunity. These advances have resulted in the implementation of gene-guided treatments, such as hematopoietic stem cell transplant for DOCK8 deficiency. However, putative disease-causing variants revealed by next-generation sequencing need rigorous validation to demonstrate pathogenicity. Here, we report the eventual diagnosis of DOCK8 deficiency in a consanguineous family due to a novel homozygous intronic deletion variant that caused aberrant exon splicing and subsequent loss of expression of DOCK8 protein. Remarkably, the causative variant was not initially detected by clinical whole-genome sequencing but was subsequently identified and validated by combining advanced genomic analysis, RNA-seq, and flow cytometry. This case highlights the need to adopt multipronged confirmatory approaches to definitively solve complex genetic cases that result from variants outside protein-coding exons and conventional splice sites. (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu Full text from SpringerLink