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

Autor: Leslie Burnett, John Reeves, Cindy S. Ma, Jennifer Stoddard, William A. Figgett, Helen C. Su, Jin Yan Yap, Gulbu Uzel, Huie Jing, Jane Peake, Paul Gray, Anna Sullivan, Bethany Pillay, Sarah K. Kummerfeld, Stuart G. Tangye, Dianne E. Campbell
Rok vydání: 2021
Předmět:
Zdroj: Journal of Clinical Immunology. 42:119-129
ISSN: 1573-2592
0271-9142
DOI: 10.1007/s10875-021-01152-x
Popis: 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.
Databáze: OpenAIRE
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