Whole genome sequencing of a sporadic primary immunodeficiency cohort

Abstract

<jats:title>Abstract</jats:title><jats:p>Primary immunodeficiency (PID) is characterised by recurrent and often life-threatening infections, autoimmunity and cancer, and it presents major diagnostic and therapeutic challenges. Although the most severe forms present in early childhood, the majority of patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent, and up to 10% develop lymphoid malignancies<jats:sup>1–3</jats:sup>. Consequently, in sporadic PID genetic diagnosis is difficult and the role of genetics is not well defined. We addressed these challenges by performing whole genome sequencing (WGS) of a large PID cohort of 1,318 participants. Analysis of coding regions of 886 index cases found disease-causing mutations in known monogenic PID genes in 10.3%, while a Bayesian approach (BeviMed<jats:sup>4</jats:sup>) identified multiple potential new candidate genes, including <jats:italic>IVNS1ABP</jats:italic>. Exploration of the non-coding genome revealed deletions in regulatory regions which contribute to disease causation. Finally, a genome-wide association study (GWAS) identified PID-associated loci and uncovered evidence for co-localisation of, and interplay between, novel high penetrance monogenic variants and common variants (at the <jats:italic>PTPN2</jats:italic> and <jats:italic>SOCS1</jats:italic> loci). This begins to explain the contribution of common variants to variable penetrance and phenotypic complexity in PID. Thus, a cohort-based WGS approach to PID diagnosis can increase diagnostic yield while deepening our understanding of the key pathways influencing human immune responsiveness.</jats:p>

Next-Generation Sequencing in the Field of Primary Immunodeficiencies: Current Yield, Challenges, and Future Perspectives

“…This study also gives an insight into the influence of multiple variants on the phenotype. In the cohort, 60 (6.8%) patients had a pathogenic TNFRSF13B (TACI) variant, with five also carrying a variant in another PID gene [18]. This study gives insight into the involvement of intergenic variation and the possibility of digenic and possibly polygenic causes of PIDs.…”

“…• Collaborative efforts are being undertaken to match patients with similar genetic defects, especially in extremely rare PIDs, for example, by using genetic matchmaking' platforms [2,5,16,17]. • WGS starts to be used as a method to explore non-coding variation and its relevance in PIDs and has recently demonstrated its potential to diagnose patients with non-coding mutations [18].…”

“…WGS has also been recently applied for the analysis of variants in PID patients. The added value of this approach was demonstrated, with the identification of compound heterozygous variants in both coding and non-coding regions [18]. However, the analysis of the vast amount of data generated by WGS is more complex than WES and more expensive, hindering its application in routine diagnostics [19].…”

“…This indicates the spectrum formed by various forms of PID, ranging from extremely rare variants leading to severe disease with a high diagnostic yield ((S)CID), rare variants leading to a milder phenotype with an intermediate diagnostic yield (CVID), and more common variants that lead to common disease with a mild phenotype and a low diagnostic yield [61,66]. The differences in the presentation of PIDs could be caused by the interplay of multiple variants in patients with milder symptoms, illustrated recently by the presence of TNFRSF13B (TACI) variants in PID patients that also presented with another pathogenic variant [18]. We postulate that genetic causes of PIDs are more common than previously thought and are inherited following The relationship between variant effect size, allele frequency, and the diagnostic success rate in the field of PIDs.…”

The genetics of human hematopoiesis and its disruption in disease

“…While many of the examples discussed above emerged through traditional family‐based linkage or sequencing analyses, as larger cohorts of rare disease patients are being assembled, broader assessments through RVAS and gene burden analyses are occurring. Such approaches have been valuable in the context of DBA (Ulirsch et al , ), as well as for studies of patients with rare congenital forms of thrombocytopenia and immunodeficiencies (preprint: Downes et al , , preprint: Thaventhiran et al , ). There is no doubt that as larger collaborative efforts are established for rare disease patients, including those with genetic blood disorders, there will be more opportunities to identify additional causal and modifier genes.…”