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Primary Immunodeficiency Study Highlights Monogenic, Common Variant Disease Contributors

NEW YORK – An international team has combined genome sequencing and genome-wide association analyses to track down high-penetrance, monogenic contributors to primary immunodeficiency (PID), along with common variants contributing to the heterogeneous conditions, within and outside of the genes implicated in monogenic forms of disease.

As they reported in Nature on Wednesday, the researchers analyzed whole-genome sequencing data for nearly 900 PID cases from the UK National Institute for Health Research BioResource-Rare Diseases (NBR-RD) program, uncovering suspicious single-gene changes — affecting known PID-related genes such as STAT1, BTK, or CTLA4 — in just over 10 percent of the cases.

From there, the team searched for additional genes and non-coding regulatory variants involved in PID, uncovering non-coding sequence deletions with apparent ties to disease. With a GWAS analyses and meta-analyses involving up to almost 800 cases and 11,000 unaffected controls, meanwhile, the investigators identified a set of common variants that appear to mediate disease risk, including SNPs falling in the major histocompatibility complex and in a region of chromosome 16.

Together, the results point to "the colocalization of — and interplay between — novel high-penetrance monogenic variants and common variants," senior and co-corresponding author Kenneth Smith, a researcher affiliated with the Cambridge Institute of Therapeutic Immunology and Infectious Disease and the University of Cambridge School of Clinical Medicine, and his colleagues wrote.

"This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID," they added.

Although past studies have highlighted hundreds of genes that appear to be involved in PID, the team noted, the heterogeneous immune conditions can be tricky to diagnose owing to the wide range of clinical features and penetrance patterns that have been described so far. That issue is exacerbated by remaining gaps in understanding all of the genetic factors that may be involved.

"Identifying a specific genetic cause of PID can facilitate definitive treatment including hematopoietic stem cell transplantation, genetic counselling, and the possibility of gene-specific therapy, and can also contribute to our understanding of the human immune system," the authors explained. "Unfortunately, a genetic cause of disease has been identified in only 29 percent of patients with PID, with the lowest rate in patients who present as adults and have no apparent family history."

For their study, the researchers did genome sequencing on 1,318 NBR-RD participants with sporadic or familial PID, focusing in on 886 individuals with PID conditions that could be clearly classified within existing diagnostic categories. Patients with adult-onset, sporadic antibody-deficiency-associated PID (AD-PID) were particularly common in the cohort, they noted.

While recurrent infections occurred across the board in the PID patients, more than a quarter of those involved in the study also experienced autoimmune symptoms and 8 percent had been diagnosed with lymphoid malignancies, a condition that has been described in up to one in 10 individuals with PID in the past.  

When they sifted through the coding and non-coding portions of the PID patient genomes, the investigators saw 91 PID cases involving pathogenic or likely pathogenic mutations in 41 genes implicated in monogenic forms of PID in the past, though the precise clinical features in those patients did not necessarily line up with those previously tied to the monogenic genes. Pathogenic changes in a PID disease modifier called TNFRSF13B turned up in five of those patients, and in dozens more individuals without monogenic disease.

Using a Bayesian inference-based analysis on sequences from 886 PID cases and 9,284 unaffected controls, the team also flagged several new candidate single-gene contributors to PID, including a gene called IVNS1ABP that was examined in more detail with expression and other data.

In a series of follow-up analyses, the researchers brought in available regulatory sequence and interaction data to search for non-coding sequences behind PID cases, and picked up additional common variant contributors with GWAS analyses that included up to 778 AD-PID cases and 10,999 controls. At least some of the suspicious common variants were over-represented in parts of the genome containing genes linked to monogenic PID, pointing to interplay between variants with a range of penetrance patterns.

"Such approaches promise to transform our understanding of genotype-phenotype relationships in PID and related immune-related conditions, and could redefine the clinical boundaries of immunodeficiency, add to our understanding of human immunology, and ultimately improve patient outcomes," the authors concluded.