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

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Abstract

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.

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Acknowledgements

We are extremely thankful to the patients and their families for participating in this study. We also thank Angela Wang (NIAID, NIH) for her regulatory assistance; the Clinical Trials & Biorepository Team, St Vincent’s Centre for Applied Medical Research (St Vincent’s Hospital, Darlinghurst, NSW Australia), for biobanking; and Dr. Karen Enthoven (CIRCA) for project coordination. Computational work was performed using the high-performance computing resources of the Garvan Institute of Medical Research. Sanger sequencing was performed by Garvan Molecular Genetics and flow cytometry by the Garvan Flow facility.

Funding

This study was supported by the NHMRC of Australia (1060303), Office of Health and Medical Research of the NSW Government, the Jeffrey Modell Foundation, SPHERE Triple I Clinical Academic Group and UNSW Medicine Infection, Immunology and Inflammation Theme, the Ross Trust, and the John Brown Cook Foundation, and in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. S.G.T was a Principal Research Fellow (1042925) of the NHMRC and is currently a recipient of an NHMRC Leadership 3 Investigator Grant (1176665) and NHMRC program grant (1113904). C.S.M is supported by an Early-Mid Career Research Fellowship from the Ministry of Health of the New South Wales Government of Australia.

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Author notes

  1. Paul E. Gray and Bethany A. Pillay contributed equally to this work.

Authors and Affiliations

  1. Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, New South Wales, 2010, Australia

    Stuart G. Tangye, Bethany A. Pillay, Jin Yan Yap, William A. Figgett, John Reeves, Sarah K. Kummerfeld, Leslie Burnett & Cindy S. Ma

  2. St Vincent’s Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia

    Stuart G. Tangye, Bethany A. Pillay, John Reeves, Leslie Burnett & Cindy S. Ma

  3. Clinical Immunogenomics Research Consortium of Australasia (CIRCA), Sydney, New South Wales, Australia

    Stuart G. Tangye, Paul E. Gray, Jin Yan Yap, Anna Sullivan, Leslie Burnett, Jane Peake & Cindy S. Ma

  4. Department of Immunology and Infectious Diseases, Sydney Children’s Hospital, Sydney, New South Wales, Australia

    Paul E. Gray

  5. School of Women’s and Children’s Health, UNSW Sydney, Sydney, New South Wales, Australia

    Paul E. Gray

  6. Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, MD, USA

    Jennifer Stoddard

  7. Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Gulbu Uzel, Huie Jing & Helen C. Su

  8. Department of Allergy and Immunology, Children’s Hospital at Westmead, Westmead, New South Wales, Australia

    Dianne E. Campbell

  9. Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia

    Dianne E. Campbell & Leslie Burnett

  10. Queensland Children’s Hospital and University of Queensland, South Brisbane, Queensland, Australia

    Anna Sullivan & Jane Peake

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  1. Stuart G. Tangye
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Contributions

SGT, PG, LB, and CSM conceived and designed the study; PG, BP, JYY, JR, WAF, SK, and CSM conducted experiments; DEC, AS, and JP provided patient care and data collection; JS and GU performed Ion Torrent, and HJ and HCS performed initial DOCK8 exon sequencing; SGT, PG, LB, and CSM supervised the study; SGT and CSM wrote drafts of the original and revised manuscripts; all authors contributed to the final version of the manuscript and approved submission of the final version.

Corresponding author

Correspondence to Cindy S. Ma.

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Ethics Approval

This study was approved by the Sydney Local Health District RPAH Zone Human Research Ethics Committee and Research Governance Office, Royal Prince Alfred Hospital, Camperdown, NSW, Australia (Protocol X16-0210/LNR/16/RPAH/257); the South East Sydney Local Health District Human Research Ethics Committee, Prince of Wales/Sydney Children’s Hospital, Randwick, NSW, Australia (Protocol HREC/11/POWH/152); and NIAID (Protocol 06-I-0015). Written informed consent was obtained from participants or their guardians.

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Patients signed informed consent regarding publishing their data.

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Tangye, S.G., Gray, P.E., Pillay, B.A. et al. Hyper-IgE Syndrome due to an Elusive Novel Intronic Homozygous Variant in DOCK8. J Clin Immunol 42, 119–129 (2022). https://doi.org/10.1007/s10875-021-01152-x

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