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

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.

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Publication Details

Journal
Journal of Clinical Immunology
Published
2024-08-05
DOI
https://doi.org/10.1007/s10875-024-01774-x
Citations
3
Primary Topic
Immunodeficiency and Autoimmune Disorders
Type
article
Field-Weighted Citation Impact
0.72

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article

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

Alberto Pinzón‐Charry, Kuang‐Chih Hsiao, Karrnan Pathmanandavel, Paul Bastard et al.
3 citations
Journal of Clinical Immunology
Immunodeficiency and Autoimmune Disorders
0.72
article

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

Alberto Pinzón‐Charry, Kuang‐Chih Hsiao, Karrnan Pathmanandavel, Paul Bastard, Patrick O’Young, Paul Gray, Geetha Rao, Karen Enthoven, Erika Della Mina, Sam McManus, Qian Zhang, Jean‐Laurent Casanova, Antoine Guérin, S. Cindy, Joseph Mackie, Stuart G. Tangye, Megan Higgins, Georgina E. Hollway, Matthew Hobbs, Fallon Noon, Melanie Wong, Anna Sullivan, Luke H. Wainwright, Aimee Huynh
article en
3 citations

Abstract

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.

Journal of Clinical ImmunologyVol. 44(8)
Griffith University (AU), Queensland Health (AU), Howard Hughes Medical Institute (US), Garvan Institute of Medical Research (AU), University of Auckland (NZ), Inserm (FR), Université Paris Cité (FR), Royal Brisbane and Women's Hospital (AU), Children's Hospital at Westmead (AU), UNSW Sydney (AU), Children’s Health Queensland Hospital and Health Service (AU), Assistance Publique – Hôpitaux de Paris (FR), St Vincent's Clinic (AU), Sydney Children's Hospital (AU), Starship Children's Health (NZ), Institut des Maladies Génétiques Imagine (FR), Western Sydney University (AU), Rockefeller University (US)
Genomic Health, University of New South Wales, Medical Research Council, National Health and Medical Research Council
Good health and well-being
Openalex Percentile: Top 29%
Immunodeficiency and Autoimmune Disorders
0.72
DOIOpen Access PDFOpenAlex
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