Eur. J. Immunol., Vol 52 (7) 2022, https://doi.org/10.1002/eji.202149480
Follicular helper T cell signature of replicative exhaustion, apoptosis, and senescence in common variable immunodeficiency
Giulia Milardi, Biagio Di Lorenzo, Jolanda Gerosa, Federica Barzaghi, Gigliola Di Matteo, Maryam Omrani, Tatiana Jofra, Ivan Merelli, Matteo Barcella, Matteo Filippini, Anastasia Conti, Francesca Ferrua, Francesco Pozzo Giuffrida, Francesca Dionisio, Patrizia Rovere‐Querini, Sarah Marktel, Andrea Assanelli, Simona Piemontese, Immacolata Brigida, Matteo Zoccolillo, Emilia Cirillo, Giuliana Giardino, Maria Giovanna Danieli, Fernando Specchia, Lucia Pacillo, Silvia Di Cesare, Carmela Giancotta, Francesca Romano, Alessandro Matarese, Alfredo Antonio Chetta, Matteo Trimarchi, Andrea Laurenzi, Maurizio De Pellegrin, Silvia Darin, Davide Montin, Maddalena Marinoni, Rosa Maria Dellepiane, Valeria Sordi, Vassilios Lougaris, Angelo Vacca, Raffaella Melzi, Rita Nano, Chiara Azzari, Lucia Bongiovanni, Claudio Pignata, Caterina Cancrini, Alessandro Plebani, Lorenzo Piemonti, Constantinos Petrovas, Raffaella Di Micco, Maurilio Ponzoni, Alessandro Aiuti, Maria Pia Cicalese, Georgia Fousteri
In the above mentioned article the peer‐reviewed tables were missing . The missing tables are shown below (Table 1, 2, 3):
Table 1.
CVID patients and healthy controls
| VARIABLES | Pediatric | Pediatric | Adult | Adult | p value |
|---|---|---|---|---|---|
| Healthy controls | CVID | Healthy controls | CVID | ||
| n | 39 | 11 | 67 | 16 | 0.8243 |
| Male, n | 20 | 8 | 20 | 9 | >0.9999 |
| (%) | 51.3% | 72.7% | 28.9% | 56.3% | |
| Age average, years | 11 | 13 | 27 | 36 | 0.8137 |
| (range) | (2‐16) | (6‐17) | (18‐52) | (20‐63) |
Table 2.
Clinical Features
| Group A (n=9) | Group B (n=18) | p value | |
|---|---|---|---|
| Splenomegaly/lymphadenopathy | 9 (100%) | 11 (61.1%) | 0.0593 |
| Autoimmune cytopenia | 7 (77.77%) | 9 (50%) | 0.2311 |
| Granuloma | 2 (22.22%) | 5 (27.77%) | 1 |
| Pulmonary disease | 6 (66.66%) | 9 (50%) | 0.4348 |
| GI disease | 3 (33.33%) | 3 (16.66%) | 0.3673 |
| >1 autoimmune diseases | 3 (33.33%) | 2 (11.11%) | 0.295 |
Table 3.
Mutations sequenced with Sanger most likely associated with CVID
| Patient (Group A) | Gene | Result | Protein change | Codon change | MAF (gnomAD Exomes) | Functional effect | HET/HOM | rs | Chromosome | Exon | CADD score PHRED | ClinVar | Varsome | SIFT/poluphen |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CVID003 | RTEL1 (NM_001283009.2) | Confirmed | p.Ala929Thr | c.2785G>A | 0,0274* | missense | HET | rs61736615 | chr20:63692937 | 29 | 2.6 | benign | benign | tolerated/benign |
| PRF1 (NM_001083116.3) | Confirmed | p.Ala91Val | c.272C>T | 0.0293 ° | missense | HET | rs35947132 | chr10:70600631 | 2 | 25 | Conflicting Interpretations of Pathogenicity | benign | deleterious/possibly damaging | |
| PRKDC (NM_006904.7) | Confirmed | p.Gly3149Asp | c.9446G>A | 0.00519 § | missense | HET | rs8178208 | chr8:47817561 | 68 | 16.92 | likely benign | benign | tolerated/benign | |
| STXBP2 (NM_006949.4) | Confirmed | p.Ala433Glu | c.1298C>A | 0,008 | missense | HET | rs141309384 | chr19:7645248 | 15 | 17.22 | / | likely benign | tolerated/benign | |
| CVID013 | INO80 (NM_17553.3) | Not confirmed | p.Ala1054Profs9* | c.3160delG | / | frameshift (deletion) | HOM | / | chr15:41313211 | 26 | / | / | / | |
| TNFRSF13C (NM_052945.4) | Confirmed | p.His159Tyr | c.475C>T | 0.00571 ç | missense | HET | rs61756766 | chr22:41925447 | 3 | 25.7 | Conflicting Interpretations of Pathogenicity | benign | deleterious/possibly damaging | |
| CVID010 | RTEL1 (NM_001283009.2) | Confirmed | p. Arg684Gln | c.2051G>A | 0,0123** | missense | HET | rs35640778 | chr20:63689775 | 24 | 22.8 | / | benign | tolerated/benign |
| TINF2 (NM_001099274.3) | Not confirmed | p.Ser245Tyr | c.734C>A | 0.000377 | missense | HET | rs142777869 | chr14:24240746 | 5 | 13.05 | likely benign | likely benign | deleterious/benign | |
| CVID017 | UNC119 (NM_005148.4) | Not confirmed | p.Tyr234Cys | c.701A>G | 0.00000796 | missense | HET | rs898900330 | chr17:28547319 | 5 | 31 | / | Uncertain significance ^ | deleterious/probably damaging |
| LYST (NM_000081.4) | Not confirmed | p.Ile632= | c.1896T>A | n.r. | synonymous variant | HET | rs1469003991 | chr1:235808922 | 5 | 6.7 | / | likely benign | ||
| CVID024 | RTEL1 (NM_001283009.2) | Confirmed | p. Arg684Gln | c.2051G>A | 0,0123** | missense | HET | rs35640778 | chr20:63689775 | 24 | 22.8 | / | benign | tolerated/benign |
| MST1 (NM_001393581.1) | Confirmed | p. Cys338Arg | c.1012T>C | 7,03E‐02 | missense | HET | rs71324987 | chr3:49686317 | 8 | 27.5 | / | Uncertain significance | ||
| TNFRSF13B (NM_012452.3) | Confirmed | p.Val220Ala | c.659T>C | 0.0162 | missense | HET | rs56063729 | chr17:16939770 | 5 | 0.81 | likely benign | benign | tolerated/benign | |
| CVID028 | PIK3CD (NM_005026.5) | Not confirmed | p.Ser312Cys | c.935C>G | 0.0202 $ | missense | HET | rs61755420 | chr1:9717541 | 8 | 19.12 | benign | benign | deleterious/benign |
| RTEL1 (NM_001283009.2) | Confirmed | p. Asn124Ser | c.371A>G | 0.0616 | missense | HET | rs3848668 | chr20:63661919 | 4 | 15.91 | benign | benign | tolerated/benign | |
| LYST (NM_000081.4) | Confirmed | p.Ser753Asn | c.2433C>T | 0.0000955 | missense | HET | rs746829669 | chr1:235808560 | 5 | 6.79 | Uncertain significance | Uncertain significance | tolerated/benign |
| Patient (Group B) | Gene | Result | Protein change | Codon change | MAF (gnomAD Exomes) | Functional effect | HET/HOM | rs | Chromosome | Exon | CADD score PHRED | ClinVar | Varsome | SIFT/poluphen |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CVID011 | NOD2 (NM_071445.1) | Not confirmed | p.Gly881Arg | c.2641G>C | 0.0113 | missense | HET | rs2066845 | chr16:50722629 | 9 | 26.5 | Conflicting Interpretations of Pathogenicity | benign | deleterious/probably damaging |
| RTEL1 (NM_001283009.2) | Not confirmed | p.Asn124Ser | c.371A>G | 0.0616 | missense | HET | rs3848668 | chr20:63661919 | 4 | 15.91 | / | benign | tolerated/benign | |
| CVID019 | STAT1(NM_007315.4) | Confirmed | p.Pro696His | c.2087C>A | 0.0000999 | missense | HET | rs138723664 | chr2:190975860 | 23 | 23.4 | Uncertain significance | Uncertain significance | tolerated/possibly damaging |
| CASP8 (NM_001372051.1) | Confirmed | p.Met1Thr | c.2T>C | 0.049 | missense | HET | rs3769824 | chr2:201258233 | 2 | 5.7 | benign | benign | tolerated/benign | |
| NOD2 (NM_071445.1) | Confirmed | p.Val955Ile | c.2863G>A | 0.0627 | missense | HET | rs5743291 | chr16:50723365 | 8 | 8.7 | likely benign | benign | deleterious/benign | |
| PRF1 (NM_001083116.3) | Confirmed | p.Ala91Val | c.272C>T | 0.0293 ° | missense | HET | rs35947132 | chr10:70600631 | 2 | 25 | Conflicting Interpretations of Pathogenicity | benign | deleterious/probably damaging | |
| T1D197 | RAG1 (NM_000448.2) | Not confirmed | a) p.Gly392Arg, b) p.Gly393Val | a) c.1174G>A, b) c.1178delG | a) 0.000012; b) 0.000014 | missense, frameshift (deletion) | HET | a) rs759928067, b) rs1554944856 | a) chr11:36574478, b) chr11:36574482 | 2 | 29.7; 28.2 | a) /; b) Conflicting Interpretations Of Pathogenicity | a) b) Uncertain significance | a) deleterious/probably damaging b) deleterious/probably damaging (la c.1178G>T) |
| TPP2 (NM_001330588.2) | Confirmed | p.Gly108Asp | c.323G>A | / | cosmic mutation | HET | COSV65752805 | chr13:102614129 | 3 | 29.2 | / | Uncertain significance |
0,0274: GnomAD exomes allele frequency = 0.0274 is greater than 0.00345 (threshold derived from the 716 clinically reported variants in gene RTEL1)
0,0123: GnomAD exomes allele frequency = 0.0123 is greater than 0.00345 (threshold derived from the 716 clinically reported variants in gene RTEL1)
0.0293 is greater than 0.00329 (threshold derived from the 251 clinically reported variants in gene PRF1)
0.00519 is greater than 0.0001 (threshold derived from the 677 clinically reported variants in gene PRKDC)
0.00571 is greater than 0.0001 (threshold derived from the 47 clinically reported variants in gene TNFRSF13C)
Pathogenic computational verdict based on 12 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM‐MKL, LIST‐S2, M‐CAP, MVP, MutationAssessor, MutationTaster, PrimateAI and SIFT vs no benign predictions.
0.0202 is greater than 0.000221 (threshold derived from the 220 clinically reported variants in gene PIK3CD)
most of the computational predictions are pathogenic