Abstract
Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited disorders, frequently caused by loss-of-function and less commonly by gain-of-function mutations, which can result in susceptibility to a broad or a very narrow range of infections but also in inflammatory, allergic or malignant diseases. Owing to the wide range in clinical manifestations and variability in penetrance and expressivity, there is an urgent need to better understand the underlying molecular, cellular and immunological phenotypes in PID patients in order to improve clinical diagnosis and management. Here we have compiled a manually curated collection of public transcriptome datasets mainly obtained from human whole blood, peripheral blood mononuclear cells (PBMCs) or fibroblasts of patients with PIDs and of control subjects for subsequent meta-analysis, query and interpretation. A total of eighteen (18) datasets derived from studies of PID patients were identified and retrieved from the NCBI Gene Expression Omnibus (GEO) database and loaded in GXB, a custom web application designed for interactive query and visualization of integrated large-scale data. The dataset collection includes samples from well characterized PID patients that were stimulated ex vivo under a variety of conditions to assess the molecular consequences of the underlying, naturally occurring gene defects on a genome-wide scale. Multiple sample groupings and rank lists were generated to facilitate comparisons of the transcriptional responses between different PID patients and control subjects. The GXB tool enables browsing of a single transcript across studies, thereby providing new perspectives on the role of a given molecule across biological systems and PID patients. This dataset collection is available at http://pid.gxbsidra.org/dm3/geneBrowser/list.
Highlights
Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited disorders, frequently caused by loss-of-function and less commonly by gain-of-function mutations, which can result in susceptibility to a broad or a very narrow range of infections and in inflammatory, allergic or malignant diseases
Any further responses from the reviewers can be found at the end of the article Introduction Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited disorders, most often caused by loss-of-function mutations and less commonly by gain-of-function mutations, affecting components of the innate and/or adaptive immune system[1,2,3]
A considerable challenge for identifying causal genetic variants—which is critical for the diagnosis and clinical management of PID patients—lies in the vast heterogeneity of the underlying immunological phenotypes and clinical manifestations on the one hand and in the degree of human genetic variation between individuals on the other hand
Summary
The ability to identify single-gene inborn errors in PID patients requires validation of the disease-causing variant by in-depth mechanistic studies demonstrating the structural and functional consequences of the mutations using blood or other accessible biological samples such as fibroblasts from skin biopsies[12] In this context, several transcriptomics studies have been conducted using whole blood, PBMCs and fibroblasts of well-characterized PID patients, to assess the underlying immunological phenotypes at the molecular and cellular levels in more detail (Table 1) and in many cases, to further validate the causal relationship between the underlying genotypes and clinical phenotypes. The GXB tool enables browsing of a single transcript across multiple studies and datasets, providing new perspectives on the role of a given molecule across biological systems and PID patients This dataset collection can aid clinicians and researchers to study and quickly visualize the functional consequences of a variety of well characterized, naturally occurring mutations on a genomewide scale
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