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

• Published in: Journal of clinical immunology Vol. 44; no. 8; p. 170
• Main Authors: Huynh, Aimee, Gray, Paul E, Sullivan, Anna, Mackie, Joseph, Guerin, Antoine, Rao, Geetha, Pathmanandavel, Karrnan, Mina, Erika Della, Hollway, Georgina, Hobbs, Matthew, Enthoven, Karen, O’Young, Patrick, McManus, Sam, Wainwright, Luke H., Higgins, Megan, Noon, Fallon, Wong, Melanie, Bastard, Paul, Zhang, Qian, Casanova, Jean-Laurent, Hsiao, Kuang-Chih, Pinzon-Charry, Alberto, Ma, Cindy S, Tangye, Stuart G.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-12-2024; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Cloning; COVID-19 - genetics; Disease prevention; Female; Gastroenteritis; Genetic disorders; Genomes; Genomic analysis; Guanine Nucleotide Exchange Factors - deficiency; Guanine Nucleotide Exchange Factors - genetics; Homozygote; Hospitals; Humans; Immunity (Disease); Immunology; Infant; Infections; Infectious Diseases; Internal Medicine; Male; Medical Microbiology; Meningitis; Mutation - genetics; Patients; Proteins; Receptor, Interferon alpha-beta - deficiency; Receptor, Interferon alpha-beta - genetics; Review; RNA Splice Sites - genetics; SARS-CoV-2 - genetics; Severe acute respiratory syndrome coronavirus 2; Vaccination; Vaccines; Viral infections; Whole genome sequencing; Polynesia
• ISSN: 0271-9142; 1573-2592; 1573-2592
• DOI: 10.1007/s10875-024-01774-x

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.