Copy Number Analysis in a Large Cohort Suggestive of Inborn Errors of Immunity Indicates a Wide Spectrum of Relevant Chromosomal Losses and Gains.

Inborn errors of immunity (IEI) are genetically driven disorders. With the advancement of sequencing technologies, a rapidly increasing number of gene defects has been identified, thereby mirroring the high heterogeneity in immunological and clinical presentations observed in patients. However, for a large majority of patients, no causative single nucleotide variant (SNV) or small indel can be identified using next-generation sequencing. First studies have shown that also copy number variants (CNVs) can cause IEI. Unfortunately, CNVs are not well examined in many routine diagnostic settings and the aim of this study was to assess the number of clinically relevant chromosomal losses and gains in a large cohort. We identified a total of 20 CNVs using whole exome sequencing data of a cohort of 191 patients with a suspected IEI. A definite molecular diagnosis could be made in five patients (2.6%), including pathogenic deletions affecting ICOS, TNFAIP3, and 22q11.2. CNVs of uncertain significance were observed in fifteen patients (7.9%), including deletions of 11q22.1q22.3 and 16p11.2 but also duplications affecting entire or parts of genes previously associated with IEI. Importantly, five patients carrying a CNV of uncertain significance also carried pathogenic or likely pathogenic SNVs (PIK3R1, NFKB1, NLRC4, DOCK2), or SNVs of unknown significance (NFKB2). This cooccurrence of SNVs and CNVs suggests modifying effects in some patients, and functional follow-up is warranted now in order to better understand phenotypic heterogeneity. In summary, the diagnostic yield of IEI can be increased substantially by evaluating CNVs, which allows an improved therapeutic management in those patients.

TET2-Driven Clonal Hematopoiesis and Response to Canakinumab: An Exploratory Analysis of the CANTOS Randomized Clinical Trial.

Importance: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of atherosclerotic cardiovascular disease, and mouse experiments suggest that CHIP related to Tet2 loss of function in myeloid cells accelerates atherosclerosis via augmented interleukin (IL) 1ß signaling. Objective: To assess whether individuals with CHIP have greater cardiovascular event reduction in response to IL-1ß neutralization in the Canankinumab Anti-inflammatory Thrombosis Outcomes Trial (CANTOS). Design, Setting, and Participants: This randomized clinical trial took place from April 2011 to June 2017 at more than 1000 clinical sites in 39 countries. Targeted deep sequencing of genes previously associated with CHIP in a subset of trial participants using genomic DNA prepared from baseline peripheral blood samples were analyzed. All participants had prior myocardial infarction and elevated high-sensitivity C-reactive protein level above 0.20 mg/dL. Analysis took place between June 2017 and December 2021. Interventions: Canakinumab, an anti-IL-1ß antibody, given at doses of 50, 150, and 300 mg once every 3 months. Main Outcomes and Measures: Major adverse cardiovascular events (MACE). Results: A total of 338 patients (8.6%) were identified in this subset with evidence for clonal hematopoiesis. As expected, the incidence of CHIP increased with age; the mean (SD) age of patients with CHIP was 66.3 (9.2) years and 61.5 (9.6) years in patients without CHIP. Unlike other populations that were not preselected for elevated C-reactive protein, in the CANTOS population variants in TET2 were more common than DNMT3A (119 variants in 103 patients vs 86 variants in 85 patients). Placebo-treated patients with CHIP showed a nonsignificant increase in the rate of MACE compared with patients without CHIP using a Cox proportional hazard model (hazard ratio, 1.32 [95% CI, 0.86-2.04]; P = .21). Exploratory analyses of placebo-treated patients with a somatic variant in either TET2 or DNMT3A (n = 58) showed an equivocal risk for MACE (hazard ratio, 1.65 [95% CI, 0.97-2.80]; P = .06). Patients with CHIP due to somatic variants in TET2 also had reduced risk for MACE while taking canakinumab (hazard ratio, 0.38 [95% CI, 0.15-0.96]) with equivocal difference compared with others (P for interaction = .14). Conclusions and Relevance: These results are consistent with observations of increased risk for cardiovascular events in patients with CHIP and raise the possibility that those with TET2 variants may respond better to canakinumab than those without CHIP. Future studies are required to further substantiate this hypothesis. Trial Registration: ClinicalTrials.gov Identifier: NCT01327846.