A Novel Case of IFNAR1 Deficiency Identified a Common Canonical Splice Site Variant in DOCK8 in Western Polynesia: The Importance of Validating Variants of Unknown Significance in Under-Represented Ancestries.

Autor: Huynh A; Queensland Paediatric Immunology and Allergy Service, Children's Health Queensland, Brisbane, QLD, 4101, Australia., Gray PE; Clinical Immunogenomics Research Consortium, Australasia, Australia.; School Medicine, Western Sydney University, Penrith, NSW, Australia.; Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Randwick, Australia., Sullivan A; Queensland Paediatric Immunology and Allergy Service, Children's Health Queensland, Brisbane, QLD, 4101, Australia.; Clinical Immunogenomics Research Consortium, Australasia, Australia., Mackie J; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia., Guerin A; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia., Rao G; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia., Pathmanandavel K; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia., Mina ED; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia., Hollway G; Clinical Immunogenomics Research Consortium, Australasia, Australia.; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia., Hobbs M; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia., Enthoven K; Clinical Immunogenomics Research Consortium, Australasia, Australia.; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia., O'Young P; Clinical Immunogenomics Research Consortium, Australasia, Australia.; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia., McManus S; Royal Brisbane and Women's Hospital, Herston, QLD, Australia., Wainwright LH; Royal Brisbane and Women's Hospital, Herston, QLD, Australia., Higgins M; Genetic Health Queensland, Brisbane, Australia., Noon F; Genetic Health Queensland, Brisbane, Australia., Wong M; Clinical Immunogenomics Research Consortium, Australasia, Australia.; Department of Allergy and Immunology, The Children's Hospital at Westmead, Sydney, NSW, Australia., Bastard P; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.; University of Paris, Imagine Institute, Paris, France.; Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France., Zhang Q; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA., Casanova JL; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.; University of Paris, Imagine Institute, Paris, France.; Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France.; Howard Hughes Medical Institute, New York, USA., Hsiao KC; Clinical Immunogenomics Research Consortium, Australasia, Australia.; Starship Child Health, Auckland, New Zealand.; Department of Paediatrics, University of Auckland, Auckland, New Zealand., Pinzon-Charry A; Queensland Paediatric Immunology and Allergy Service, Children's Health Queensland, Brisbane, QLD, 4101, Australia.; Clinical Immunogenomics Research Consortium, Australasia, Australia.; Griffith University and University of Queensland, Queensland, Australia., Ma CS; Clinical Immunogenomics Research Consortium, Australasia, Australia.; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia., Tangye SG; Clinical Immunogenomics Research Consortium, Australasia, Australia. s.tangye@garvan.org.au.; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia. s.tangye@garvan.org.au.; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia. s.tangye@garvan.org.au.
Jazyk: angličtina
Zdroj: Journal of clinical immunology [J Clin Immunol] 2024 Aug 05; Vol. 44 (8), pp. 170. Date of Electronic Publication: 2024 Aug 05.
DOI: 10.1007/s10875-024-01774-x
Abstrakt: Advanced genomic technologies such as whole exome or whole genome sequencing have improved diagnoses and disease outcomes for individuals with genetic diseases. Yet, variants of unknown significance (VUS) require rigorous validation to establish disease causality or modification, or to exclude them from further analysis. Here, we describe a young individual of Polynesian ancestry who in the first 13 mo of life presented with SARS-CoV-2 pneumonia, severe enterovirus meningitis and adenovirus gastroenteritis, and severe adverse reaction to MMR vaccination. Genomic analysis identified a previously reported pathogenic homozygous variant in IFNAR1 (c.1156G > T, p.Glu386* LOF), which is common in Western Polynesia. Moreover, a new and putatively deleterious canonical splice site variant in DOCK8 was also found in homozygosity (c.3234 + 2T > C). This DOCK8 variant is common in Polynesians and other under-represented ancestries in large genomic databases. Despite in silico bioinformatic predictions, extensive in vitro and ex vivo analysis revealed the DOCK8 variant likely be neutral. Thus, our study reports a novel case of IFNAR1 deficiency, but also highlights the importance of functional validation of VUS, including those predicted to be deleterious, and the pressing need to expand our knowledge of the genomic architecture and landscape of under-represented populations and ancestries.
(© 2024. The Author(s).)
Databáze: MEDLINE
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