The impact of rare and low-frequency genetic variants in common variable immunodeficiency (CVID)

Abstract

Next Generation Sequencing (NGS) has uncovered hundreds of common and rare genetic variants involved in complex and rare diseases including immune deficiencies in both an autosomal recessive and autosomal dominant pattern. These rare variants however, cannot be classified clinically, and common variants only marginally contribute to disease susceptibility. In this study, we evaluated the multi-gene panel results of Common Variable Immunodeficiency (CVID) patients and argue that rare variants located in different genes play a more prominent role in disease susceptibility and/or etiology. We performed NGS on DNA extracted from the peripheral blood leukocytes from 103 patients using a panel of 19 CVID-related genes: CARD11, CD19, CD81, ICOS, CTLA4, CXCR4, GATA2, CR2, IRF2BP2, MOGS, MS4A1, NFKB1, NFKB2, PLCG2, TNFRSF13B, TNFRSF13C, TNFSF12, TRNT1 and TTC37. Detected variants were evaluated and classified based on their impact, pathogenicity classification and population frequency as well as the frequency within our study group. NGS revealed 112 different (a total of 227) variants with under 10% population frequency in 103 patients of which 22(19.6%) were classified as benign, 29(25.9%) were classified as likely benign, 4(3.6%) were classified as likely pathogenic and 2(1.8%) were classified as pathogenic. Moreover, 55(49.1%) of the variants were classified as variants of uncertain significance. We also observed different variant frequencies when compared to population frequency databases. Case–control data is not sufficient to unravel the genetic etiology of immune deficiencies. Thus, it is important to understand the incidence of co-occurrence of two or more rare variants to aid in illuminating their potential roles in the pathogenesis of immune deficiencies.

Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

“…Finding novel variants in a known gene, especially if classified with an uncertain significance, may require additional investigations to prove their association with specific phenotypic patterns [28], that is, more than mere in silico predictions [48,49]. The effect of some variants of the CASP10 and PIK3CD genes, found in patients showing symptoms and laboratory alterations similar to ALPS patients (the so-called ALPS undefined, or ALPS-U), but not fully matching the 2009 NIH revised diagnostic criteria [11], was investigated through proper functional tests, allowing confirmation of their postulated pathogenicity [34,44,45].…”

“…The TNFRSF13B and TNFRSF13C genes also provided variants illustrating the often complicated and unclear genotype-phenotype correlations. Indeed, mutations of the former gene, also known as TACI, though rare, have already shown to vary between disease susceptibility and pathogenesis, with clinical presentation ranging from unaffected to severe immunodeficiency and also occurring in healthy controls [49,52,53]. Nonetheless, asymptomatic family members have been reported with detectable in vitro B cell defects, thus suggesting that the penetrance of some mutations could be higher in cells than for the clinical phenotype [54].…”

Clinical exome sequencing data from patients with inborn errors of immunity: cohort level meta-analysis and the benefit of systematic reanalysis

“…Conforming to ample literature describing an enrichment of these three variants in patients with common variable immunodeficiency (CVID), we found a higher carrier proportion among patients with PAD compared to the rest of the cohort (31/204, 15.2%), including 19 carriers of p.(Cys104Arg) (9.3%, 17 heterozygotes, 2 homozygotes) (56–58). In addition, the p.(Arg20Cys) variant that was identified in 3 individuals (two with PAD/CVID, one with autoinflammation) has not been characterized as a risk factor for PAD but has been put forward as a candidate variant (59– 61). Of the 34 PAD patients that carried a risk variant, antibody deficiency was confirmed in 29 patients (93.5%) based on additional clinical information.…”

Did variants in inborn errors of immunity genes contribute to the extinction of Neanderthals?

“…The variant in the MOGS gene (NM_006302(MOGS):c.1484G>A,p.R495Q (rs34075781, CADD: 23.7)) is in the C-terminal catalytic domain (Figure 2B). This variant has a 0.0001 allele frequency in controls and was reported as a variant of unknown significance (VUS) in 2021 in a patient with common variable immunodeficiency (CVID) ( 39 ).…”