Table 1.
Genetic alterations identified through different next generation platforms in CVID samples. A Disintegrin and Metalloproteinase (ADAM); Activation induced cytidine deaminase (AICDA); Adenosine deaminase 2 (ADA2); AKT serine/threonine kinase 1 (AKT1); ATM Serine/Threonine kinase (ATM); B-cell lymphoma 2 like 1 (BCL2L1); B-cell lymphoma 6 (BCL6); C–C chemokine receptor type 7 (CCR7); CD40 ligand (CD40LG); CD 81 molecule (CD81); Cat eye syndrome chromosome region, candidate 1 (CECR1); Complement factor H related 5 (CFHR5); Chromodomain helicase DNA binding protein 7 (CHD7); Cytotoxic T-lymphocyte associated protein 4 (CTLA4); DNA methyltransferase 3 beta (DNMT3B); Dedicator of cytokinesis 8 (DOCK8); Desmoglein 1 (DSG1); Ectopic P-granules autophagy protein 5 (EPG5); Forkhead Box O(FOXO); Intercellular adhesion molecule 1 (ICAM1); Interferon (IFN); DNA Ligase 1 (LIG1); Fatty acid synthase (FASN); Fibrillin-1 (FBN1); Inhibitor of nuclear factor kappa B kinase regulatory subunit gamma (IKBKG); IKAROS family zinc finger 1 (IKZF1); Interleukin 1 alpha (IL1A); Interferon regulatory factor 2 binding protein 2 (IRF2BP2); Lymphocyte transmembrane adaptor 1 (LAX1); Lipopolysaccharide-responsive beige-like anchor protein (LRBA); Leucine rich repeat containing 8 VRAC subunit A (LRRC8A); Mitogen-activated protein kinase 8 (MAPK8); Mannan binding lectin serine peptidase 2 (MASP2); Mediterranean fever (MEFV); MX domain like GTPase 1 (MX1); NBPF member 15 (NBPF15); Neutrophil cytosolic factor 2 (NCF2); Nuclear factor kappa B subunit 1 (NFKB1); Nuclear factor kappa B subunit 2 (NFKB2); NLR family pyrin domain containing 3 (NLRP3); NLR family pyrin domain containing 12 (NLRP12); Paired Box 5 (PAX5); Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD); Phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1); Phospholipase C, gamma (PLCG); Protein kinase C delta (PRKCD); Protein tyrosine phosphatase receptor type C (PTPRC); Recombination activating 1 (RAG1); Recombination activating 2 (RAG2); Retinoblastoma associated (RBA); Potassium calcium-activated channel subfamily N member 4 (KCNN4); Ribosomal protein S6 kinase beta-2 (RPS6KB2); Splicing factor 3b subunit 1 (SF3B1); Signal transducer and activator of transcription 1 (STAT1); Signal transducer and activator of transcription 3 (STAT3); Syntaxin binding protein 2 (STXBP2); Transcription factor 3 (TCF3); Toll like receptor 1 (TLR1); TNF receptor superfamily member 13B (TNFRSF13B); TRAF3 interacting protein 2 (TRAF3IP2); Tubulin beta 1 class VI (TUBB1); Tyrosine kinase 2 (TYK2); Unc-13 homolog D (UNC13D); Zinc finger and BTB domain containing 24 (ZBTB24).
| Technique | Patients Enrolled in study | Genes Alterations/Mutation | Year | Reference |
|---|---|---|---|---|
| Next Generation Sequencing Technology | ||||
| Hyper-IgM/CVID custom 148 gene Re-sequencing chip | 34 CVID patients | TNFRSF13B,AICDA,CD40LG, IKBKG, TRAF3IP2 | 2010 | 31 |
| Genome-wide SNP genotyping (InfiniumII HumanHap610 BeadChip) | 363 CVID patients | CVID association with ADAM and MHC genes. | 2011 | 32 |
| IGH rearrangements (Roche 454 sequencing) | 18 CVID patients | VDJ rearrangement and abnormal formation of complementarity determining region 3 (CDR3) | 2015 | 33 |
| High-throughput DNA sequencing of immunoglobulin heavy chain gene rearrangements (Roche 454 DNA sequencing) | 93 CVID patients | VDJ rearrangement and abnormal formation of complementarity determining region 3 (CDR3) | 2015 | 35 |
| Whole exome sequencing (1st patient) and Targeted Gene Panel (2nd patient) | 2 CVID patients | 1st Patient: RAG1 (c256_257delAA, c1835A > G) 2nd Patient: RAG1(c.1566G > T, c.2689C > T) |
2015 | 37 |
| Targeted PID gene sequencing (Ion PGM) | 1CVID patient | RAG1 mutation (c.1871G > A, c.2182T > C and p.H249R) | 2016 | 38 |
| Next-generation sequencing of TCRbrepertoire (ClonoSIGHT platform (Sequenta) | 42 CVID patients | Decrease in TCR repertoire diversity, naive T cells, and thymic volume was consistent with orthogonal evidence supporting thymic failure in CVID patients. | 2016 | 40 |
| Whole exome sequencing | A family with 3 affected individuals with CVID and unaffected family members | Novel mutation IRF2BP2 (c.1652G > A:p(S551N)) | 2016 | 41 |
| Targeted exome sequencing (Illumnia HiSeq 3000) | 1 patient | Novel frameshift mutation in NFKB1c.491delG (p.G165A*31) | 2016 | 42 |
| Whole exome sequencing | 5 family members of CVID patient | Two Heterozygous mutation in CECR1 (encoding ADA2) rs77563738 and novel Chr22:17,684,478 A > C) | 2016 | 44 |
| Whole exome sequencing (IlluminaHiSeq 2500) | 50 CVID patients | Monoallelic mutations (NFKB1, STAT3, CTLA4, PIK3CDand IKZF1) Biallelic mutations (LRBA and STXBP2) | 2016 | 25 |
| Targeted Sequencing (MiSeq (Illumina)) | 1 patient | RAG1: Three mutations. Two Novel:A missense variant (c.1123C > G) and frameshift deletion (c.1430delC, p.F478Sfs*14) and a known missense mutation (c.1420C > T, rs199474678) | 2017 | 39 |
| Whole exome sequencing (HiSeq 2000 or NextSeq 500 (Illumina)) | 7 CVID patients | STAT1, NLRP3, MEFV, TNSFR13B, LIG1, MX1, FBN1, DSG1, UNC13D, TLR1, NBPF15, FASN, IL1A, LAX1, SF3B1, CHD7, TUBB1, ATM, TYK2, LRRC8A, PRKDC, CFHR5, LRBA, EPG5, RAG2, RAG1, NCF2, PTPRC and MASP2 mutations. | 2017 | 45 |
| TCRβ High-throughput sequencing (Adaptive Biotechnologies) | 44 CVID patients | CVID TCRs had reduced junctional diversity and CVID CD3 sequence had increased clonality. | 2017 | 34 |
| Targeted Sequencing (MiSeq (Illumina)) | 1 patient | NFKB1frameshift mutation (c.1149delT, p.Gly384Glu ∗ 48) | 2018 | 43 |
| TCR Repertoire sequencing (Roche 454 sequencing) | 33 CVID patients | CVID patients had defective V(D)J recombination along with somatic Hyper-mutation (SHM). | 2018 | 36 |
| Whole exome sequencing (IlluminaHiseq 4000) | 3 CVID patients | 1st patient:RBA (c.8436G > C and c.4089A > T) and TNFRSF13B (c.226G > A) 2nd patient: LRBA (c.3764G > C) 3rd patient: LRBA (c.5084T > C) and NFKB1 (c.666dupG). |
2018 | 47 |
| Whole exome sequencing (IlluminaHiSeq 2000) | 36 CVID patients | LRBA, CTLA4, NFKB1,PIK3R1, PRKCD, MAPK8and DOCK8 | 2018 | 48 |
| Whole exome sequencing | 550 patients (HIgM, CVID and Agammaglobulinemia) | LRBA, ZBTB24andDNMT3Bmutations in CVID | 2018 | 49 |
| Transcriptome Expression | ||||
| GeneChip Human Genome U133A Array (Affymetrix) | 23 CVID patients | Enhanced cytotoxic effector functions, Predominance of CCR7-T cells, and Antigen activated T cells | 2004 | 50 |
| HT-12 V4 BeadChip (Illumina) | 91 CVID patients | Up-regulation of IFN responsive genes. | 2013 | 51 |
| Whole transcriptome sequencing (IlluminaHiSeq 2000) | 1 patient | NLRP12 (Heterozygous mutations) encoding NALP12 protein (p.H304Y and p.A629D) | 2014 | 52 |
| RNA sequencing (IlluminaHiSeq 2500) | 3 CVID patients | TNFRSF13B, LRBA, NLRP12and TNFRSF13Cvariants and up-regulation of NLRP12, ICAM1, CD81 and PLCG. | 2015 | 7 |
| RNA sequencing (IlluminaHiSeq 2000) | 7 equine CVID patients | Down-regulation of pro-B cell differentiation genes specifically PAX5 | 2015 | 56 |
| Epigenetic Alterations | ||||
| High-Throughput DNA methylation and Bisulfite-modified DNA pyrosequencing | 23 CVID patients | Impaired demethylation in AICDA, BCL6, STAT3, FOXO, AKT1 and NFKB2 | 2019 | 60 |
| High-Throughput DNA methylation | Monozygotic twins discordant for CVID | PIK3CD, BCL2L1, RPS6KB2, TCF3 and KCNN4 | 2015 | 55 |
| Genome wide bisulfite sequencing | Seven equine CVID patients | PAX5 gene silencing | 2015 | 56 |