Genetic Testing Program for Activated PI3K Delta Syndrome (APDS)

PGmax™ - Inborn Errors of Immunity/Primary Immunodeficiency (PID) Panel

Test Code: 13999, includes 640 Genes

Genes: ACD, ACP5, ACTB, ADA, ADA2, ADAM17, ADAMTS13, ADAMTS3, ADAR, ADIPOQ, ADIPOR1, ADIPOR2, AICDA, AIRE, AK2, ALG6, ALPI, ANGPT1, ANKZF1, AP1S3, AP3B1, AP3D1, APOA1, APOA2, APOL1, ARHGEF1, ARPC1B, ASAH1, ATM, ATP6AP1, ATR, B2M, BACH2, BCL10, BCL11B, BLM, BLNK, BLOC1S3, BLOC1S6, BRIP1, BTK, C1QA, C1QB, C1QBP, C1QC, C1R, C1S, C2, C2orf69, C3, C3AR1, C4BPA, C4BPB, C5, C5AR1, C5AR2, C6, C7, C8A, C8B, C8G, C9, CARD11, CARD14, CARD8, CARD9, CARMIL2, CASP10, CASP8, CAVIN1, CBL, CCBE1, CCDC103, CCDC39, CCDC40, CCDC65, CCNO, CD19, CD247, CD27, CD3D, CD3E, CD3G, CD40, CD40LG, CD46, CD55, CD59, CD70, CD79A, CD79B, CD81, CD8A, CD93, CDC42, CDCA7, CDK9, CEBPE, CENPF, CFAP298, CFAP300, CFB, CFD, CFH, CFI, CFP, CFTR, CHD7, CHUK, CIB1, CIITA, CLCN7, CLEC7A, CLPB, CLU, COG6, COL7A1, COLEC11, COPA, CORO1A, CR2, CREBBP, CRP, CSF2RA, CSF2RB, CSF3R, CTC1, CTLA4, CTPS1, CTSC, CXCR2, CXCR4, CYBA, CYBB, CYBC1, CYP27A1, DBR1, DCLRE1B, DCLRE1C, DEF6, DGAT1, DGKE, DHFR, DIAPH1, DKC1, DNAAF1, DNAAF11, DNAAF2, DNAAF3, DNAAF4, DNAAF5, DNAAF6, DNAH1, DNAH11, DNAH5, DNAH9, DNAI1, DNAI2, DNAJB13, DNAJC21, DNAL1, DNASE1L3, DNASE2, DNMT3B, DOCK11, DOCK2, DOCK8, DRC1, DSG1, DTNBP1, DUOX2, EBF1, EFL1, EIF2AK3, ELANE, ELF4, EPG5, EPO, ERBIN, ERCC2, ERCC3, ERCC4, ERCC6L2, ETV6, EXTL3, F11, F13A1, F13B, F5, F7, F8, F9, FAAP24, FADD, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FAS, FASLG, FAT4, FCHO1, FCN1, FCN2, FCN3, FERMT1, FERMT3, FGA, FGB, FNIP1, FOXI3, FOXJ1, FOXN1, FOXP3, FPR1, G6PC1, G6PC3, G6PD, GAS2L2, GAS8, GATA1, GATA2, GFI1, GINS1, GP1BA, GP1BB, GP9, GTF2E2, GTF2H5, GUCY2C, HAVCR2, HAX1, HCK, HELLS, HMOX1, HPS1, HPS3, HPS4, HPS5, HPS6, HTR1A, HTRA2, HYOU1, ICOS, IFIH1, IFNAR1, IFNAR2, IFNG, IFNGR1, IFNGR2, IGHM, IGKC, IGLL1, IKBKB, IKBKG, IKZF1, IKZF2, IKZF3, IL10, IL10RA, IL10RB, IL12B, IL12RB1, IL12RB2, IL17F, IL17RA, IL17RC, IL1RN, IL2, IL21, IL21R, IL23R, IL2RA, IL2RB, IL2RG, IL36RN, IL6R, IL6ST, IL7R, INO80, INSR, INVS, IRAK1, IRAK4, IRF2BP2, IRF3, IRF4, IRF7, IRF8, IRF9, ISG15, ITCH, ITGAM, ITGB2, ITK, ITPKB, IVNS1ABP, JAGN1, JAK1, JAK2, JAK3, KCNN4, KDM6A, KIT, KMT2A, KMT2D, KRAS, LAMTOR2, LAT, LCK, LCT, LIG1, LIG4, LIPA, LPIN2, LRBA, LRRC56, LRRC8A, LSM11, LYN, LYST, MAD2L2, MAGT1, MALT1, MAN2B1, MAN2B2, MANBA, MAP3K14, MAPK8, MASP1, MASP2, MAT2A, MBL2, MC2R, MCIDAS, MCM10, MCM4, MEFV, MLPH, MOGS, MPL, MPLKIP, MPO, MRE11, MRTFA, MS4A1, MSN, MTHFD1, MVK, MYD88, MYH9, MYO5A, MYO5B, MYSM1, NBAS, NBN, NCF2, NCF4, NCKAP1L, NCSTN, NEUROG3, NFAT5, NFE2L2, NFKB1, NFKB2, NFKBIA, NHEJ1, NHP2, NKX2-5, NLRC4, NLRP1, NLRP12, NLRP3, NME8, NOD2, NOP10, NOS2, NRAS, NSMCE3, OAS1, ODAD1, ODAD2, ODAD3, ODAD4, OFD1, ORAI1, OSTM1, OTULIN, PALB2, PARN, PAX1, PCCA, PCCB, PDCD1, PEPD, PGM3, PI4KA, PIGA, PIK3CD, PIK3CG, PIK3R1, PLCG2, PLG, PMM2, PMS2, PNP, POLA1, POLD1, POLD2, POLE, POLE2, POLR3A, POLR3C, POLR3F, POMP, PRF1, PRG4, PRKCD, PRKDC, PROC, PROS1, PSENEN, PSMA3, PSMB4, PSMB8, PSMB9, PSMG2, PSTPIP1, PTEN, PTPRC, PTX3, RAB27A, RAC2, RAD50, RAD51C, RAG1, RAG2, RANBP2, RASGRP1, RBCK1, RBM8A, RECQL4, REL, RELA, RELB, RFWD3, RFX5, RFXANK, RFXAP, RHOG, RHOH, RIGI, RIPK1, RMRP, RNASEH2A, RNASEH2B, RNASEH2C, RNF113A, RNF168, RNF31, RNU4ATAC, RNU7-1, RORC, RPGR, RPL11, RPL15, RPL17, RPL18, RPL19, RPL26, RPL27, RPL31, RPL35, RPL35A, RPL36, RPL5, RPS10, RPS15, RPS15A, RPS17, RPS19, RPS20, RPS24, RPS26, RPS27, RPS27A, RPS28, RPS29, RPS7, RPSA, RSPH1, RSPH3, RSPH4A, RSPH9, RTEL1, RUNX1, SAMD9, SAMD9L, SAMHD1, SAR1B, SASH3, SBDS, SCO2, SEC61A1, SEMA3E, SERPING1, SH2D1A, SH3BP2, SH3KBP1, SI, SIAE, SKIC2, SKIC3, SLC10A2, SLC26A3, SLC29A3, SLC35A1, SLC35C1, SLC37A4, SLC39A4, SLC39A7, SLC46A1, SLC5A1, SLC7A7, SLC9A3, SLX4, SMARCAL1, SMARCD2, SNX10, SOCS1, SP110, SPAG1, SPI1, SPINK5, SPINT2, SPPL2A, SRP54, SRP72, SRPRA, STAT1, STAT2, STAT3, STAT4, STAT5B, STIM1, STING1, STK36, STK4, STN1, STX11, STX3, STXBP2, SYK, TAFAZZIN, TAOK2, TAP1, TAP2, TAPBP, TBK1, TBX1, TBX21, TBXAS1, TCF3, TCIRG1, TCN2, TERC, TERT, TET2, TFRC, TGFB1, TGFBR1, TGFBR2, THBD, THPO, TICAM1, TIMM50, TINF2, TIRAP, TLR3, TLR7, TLR8, TMC6, TMC8, TNFAIP3, TNFRSF11A, TNFRSF13B, TNFRSF13C, TNFRSF1A, TNFRSF4, TNFRSF6B, TNFRSF9, TNFSF11, TNFSF12, TONSL, TOP2B, TP63, TPP1, TPP2, TRAC, TRADD, TRAF3, TRAF3IP2, TREX1, TRIM22, TRNT1, TTC12, TTC7A, TYK2, UBE2T, UNC119, UNC13D, UNC45A, UNC93B1, UNG, USB1, USP18, VAV1, VPS13B, VPS45, VSIG4, VTN, WAS, WDR1, WIPF1, WRAP53, XIAP, XK, XRCC2, ZAP70, ZBTB24, ZCCHC8, ZMYND10, ZNF341, ZNFX1

PGmax™ - Primary Immunodeficiency and Malignancy Predisposition Panel

Test Code: 19998, includes 712 Genes

Genes: ABCB7, ABCG5, ABCG8, ACD, ACP5, ACTB, ACTN1, ADA, ADA2, ADAM17, ADAMTS13, ADAMTS3, ADAR, ADIPOQ, ADIPOR1, ADIPOR2, AICDA, AIRE, AK2, ALAS2, ALG6, ALPI, ANGPT1, ANKRD26, ANKZF1, AP1S3, AP3B1, AP3D1, APOA1, APOA2, APOL1, ARHGEF1, ARPC1B, ASAH1, ATM, ATP6AP1, ATR, ATRX, B2M, BACH2, BCL10, BCL11B, BLM, BLNK, BLOC1S3, BLOC1S6, BRAF, BRCA1, BRCA2, BRIP1, BTK, C1QA, C1QB, C1QBP, C1QC, C1R, C1S, C2, C2orf69, C3, C3AR1, C4BPA, C4BPB, C5, C5AR1, C5AR2, C6, C7, C8A, C8B, C8G, C9, CARD11, CARD14, CARD8, CARD9, CARMIL2, CASP10, CASP8, CAVIN1, CBL, CCBE1, CCDC103, CCDC39, CCDC40, CCDC65, CCNO, CD19, CD247, CD27, CD3D, CD3E, CD3G, CD40, CD40LG, CD46, CD55, CD59, CD70, CD79A, CD79B, CD81, CD8A, CD93, CDAN1, CDC42, CDCA7, CDIN1, CDK9, CDKN2A, CEBPA, CEBPE, CENPF, CFAP298, CFAP300, CFB, CFD, CFH, CFI, CFP, CFTR, CHD7, CHEK2, CHUK, CIB1, CIITA, CLCN7, CLEC7A, CLPB, CLU, COG6, COL7A1, COLEC11, COPA, CORO1A, CR2, CREBBP, CRP, CSF2RA, CSF2RB, CSF3R, CTC1, CTLA4, CTPS1, CTSC, CXCR2, CXCR4, CYBA, CYBB, CYBC1, CYCS, CYP27A1, DBR1, DCLRE1B, DCLRE1C, DDX11, DDX41, DEF6, DGAT1, DGKE, DHFR, DIAPH1, DKC1, DNAAF1, DNAAF11, DNAAF2, DNAAF3, DNAAF4, DNAAF5, DNAAF6, DNAH1, DNAH11, DNAH5, DNAH9, DNAI1, DNAI2, DNAJB13, DNAJC21, DNAL1, DNASE1L3, DNASE2, DNMT3A, DNMT3B, DOCK11, DOCK2, DOCK8, DRC1, DSG1, DTNBP1, DUOX2, EBF1, EFL1, EIF2AK3, ELANE, ELF4, EPCAM, EPG5, EPO, ERBIN, ERCC2, ERCC3, ERCC4, ERCC6L2, ETV6, EXTL3, F11, F13A1, F13B, F5, F7, F8, F9, FAAP24, FADD, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FAS, FASLG, FAT4, FCHO1, FCN1, FCN2, FCN3, FERMT1, FERMT3, FGA, FGB, FLI1, FNIP1, FOXI3, FOXJ1, FOXN1, FOXP3, FPR1, FYB1, G6PC1, G6PC3, G6PD, GAS2L2, GAS8, GATA1, GATA2, GFI1, GFI1B, GINS1, GLRX5, GP1BA, GP1BB, GP9, GTF2E2, GTF2H5, GUCY2C, HAVCR2, HAX1, HCK, HELLS, HLTF, HMOX1, HOXA11, HPS1, HPS3, HPS4, HPS5, HPS6, HSPA9, HTR1A, HTRA2, HYOU1, ICOS, IFIH1, IFNAR1, IFNAR2, IFNG, IFNGR1, IFNGR2, IGHM, IGKC, IGLL1, IKBKB, IKBKG, IKZF1, IKZF2, IKZF3, IL10, IL10RA, IL10RB, IL12B, IL12RB1, IL12RB2, IL17F, IL17RA, IL17RC, IL1RN, IL2, IL21, IL21R, IL23R, IL2RA, IL2RB, IL2RG, IL36RN, IL6R, IL6ST, IL7R, INO80, INSR, INVS, IRAK1, IRAK4, IRF2BP2, IRF3, IRF4, IRF7, IRF8, IRF9, ISG15, ITCH, ITGA2, ITGA2B, ITGAM, ITGB2, ITGB3, ITK, ITPKB, IVNS1ABP, JAGN1, JAK1, JAK2, JAK3, KCNN4, KDM1A, KDM6A, KIF23, KIT, KLF1, KLHDC8B, KMT2A, KMT2D, KRAS, LAMTOR2, LAT, LCK, LCT, LIG1, LIG4, LIPA, LPIN2, LRBA, LRRC56, LRRC8A, LSM11, LYN, LYST, MAD2L2, MAGT1, MALT1, MAN2B1, MAN2B2, MANBA, MAP3K14, MAPK8, MASP1, MASP2, MASTL, MAT2A, MBD4, MBL2, MC2R, MCIDAS, MCM10, MCM4, MECOM, MEFV, MLH1, MLPH, MOGS, MPIG6B, MPL, MPLKIP, MPO, MRE11, MRTFA, MS4A1, MSH2, MSH6, MSN, MTHFD1, MVK, MYD88, MYH9, MYO5A, MYO5B, MYSM1, NAF1, NBAS, NBEAL2, NBN, NCF2, NCF4, NCKAP1L, NCSTN, NEUROG3, NF1, NFAT5, NFE2L2, NFKB1, NFKB2, NFKBIA, NHEJ1, NHP2, NKX2-5, NLRC4, NLRP1, NLRP12, NLRP3, NME8, NOD2, NOP10, NOS2, NPAT, NPM1, NRAS, NSMCE3, OAS1, ODAD1, ODAD2, ODAD3, ODAD4, OFD1, ORAI1, OSTM1, OTULIN, PALB2, PARN, PAX1, PAX5, PCCA, PCCB, PDCD1, PEPD, PGM3, PI4KA, PIEZO1, PIGA, PIK3CD, PIK3CG, PIK3R1, PLCG2, PLG, PMM2, PMS2, PNP, POLA1, POLD1, POLD2, POLE, POLE2, POLR3A, POLR3C, POLR3F, POMP, POT1, PRF1, PRG4, PRKACG, PRKCD, PRKDC, PROC, PROS1, PSENEN, PSMA3, PSMB4, PSMB8, PSMB9, PSMG2, PSTPIP1, PTEN, PTPN11, PTPRC, PTPRJ, PTPRU, PTX3, PUS1, RAB27A, RAC2, RAD23B, RAD50, RAD51, RAD51C, RAD51D, RAG1, RAG2, RANBP2, RASGRP1, RBCK1, RBM8A, RECQL4, REL, RELA, RELB, RFWD3, RFX5, RFXANK, RFXAP, RHOG, RHOH, RIGI, RIPK1, RMRP, RNASEH2A, RNASEH2B, RNASEH2C, RNF113A, RNF168, RNF31, RNU4ATAC, RNU7-1, RORC, RPGR, RPL11, RPL15, RPL17, RPL18, RPL19, RPL26, RPL27, RPL31, RPL35, RPL35A, RPL36, RPL5, RPS10, RPS14, RPS15, RPS15A, RPS17, RPS19, RPS20, RPS24, RPS26, RPS27, RPS27A, RPS28, RPS29, RPS7, RPSA, RSPH1, RSPH3, RSPH4A, RSPH9, RTEL1, RUNX1, SAMD14, SAMD9, SAMD9L, SAMHD1, SAR1B, SASH3, SBDS, SBF2, SCO2, SEC23B, SEC61A1, SEMA3E, SEPTIN6, SERPING1, SETBP1, SH2B3, SH2D1A, SH3BP2, SH3KBP1, SI, SIAE, SKIC2, SKIC3, SLC10A2, SLC19A2, SLC25A38, SLC26A3, SLC29A3, SLC35A1, SLC35C1, SLC37A4, SLC39A4, SLC39A7, SLC46A1, SLC5A1, SLC7A7, SLC9A3, SLX4, SMARCAL1, SMARCD2, SMPD1, SNX10, SOCS1, SP110, SPAG1, SPI1, SPINK5, SPINT2, SPPL2A, SRP54, SRP72, SRPRA, STAT1, STAT2, STAT3, STAT4, STAT5B, STIM1, STING1, STK36, STK4, STN1, STX11, STX3, STXBP2, SYK, TAFAZZIN, TAOK2, TAP1, TAP2, TAPBP, TBK1, TBX1, TBX21, TBXAS1, TCF3, TCIRG1, TCN2, TERC, TERF2IP, TERT, TET2, TFRC, TGFB1, TGFBR1, TGFBR2, THBD, THPO, TICAM1, TIMM50, TINF2, TIRAP, TLR3, TLR7, TLR8, TMC6, TMC8, TNFAIP3, TNFRSF11A, TNFRSF13B, TNFRSF13C, TNFRSF1A, TNFRSF4, TNFRSF6B, TNFRSF9, TNFSF11, TNFSF12, TONSL, TOP2B, TP53, TP63, TPP1, TPP2, TRAC, TRADD, TRAF3, TRAF3IP2, TREX1, TRIM22, TRNT1, TSR2, TTC12, TTC7A, TUBB1, TYK2, UBA1, UBE2T, UNC119, UNC13D, UNC45A, UNC93B1, UNG, USB1, USP18, VAV1, VPS13B, VPS45, VSIG4, VTN, WAS, WDR1, WIPF1, WRAP53, XIAP, XK, XRCC2, ZAP70, ZBTB24, ZCCHC8, ZMYND10, ZNF341, ZNFX1

Family Targeted Testing

Relatives of program participants who receive a PIK3CD or PIK3R1 Pathogenic, Likely Pathogenic or Variant of Uncertain Significance (VUS) result are eligible to receive Family Targeted Variant Testing at no additional charge.

Test Code 100: Targeted Sanger Sequencing of (1) PIK3CD or PIK3R1 variant (Pathogenic, Likely Pathogenic or Variant of Uncertain Significance (VUS)).

Test Code 200: Targeted Sanger Sequencing of (2) PIK3CD or PIK3R1 variants (Pathogenic, Likely Pathogenic or Variant of Uncertain Significance (VUS)).

PGmax™ - Inborn Errors of Immunity/Primary Immunodeficiency (PID) Panel

There are currently over 400 different inborn errors of immunity, also referred to as primary immunodeficiencies (PID) that range in severity and age of onset. PIDs, when considered individually, were previously considered rare diseases with an incidence ranging from ~1 in 10,000 to 1 in 50,000 births; however, when considered collectively and with improved definitions of clinical phenotypes and newborn screening the incidence may be closer to ~1 in 1,000 to 1 in 5,000 births (Griffith et al. 2016. PubMed ID: 27262745; Tangye et al. 2020. PubMed ID: 31953710). PIDs encompass a variety of different disorder subclasses including antibody deficiencies, autoinflammatory disorders, combined immunodeficiencies, diseases of immune dysregulation, congenital defects in phagocyte function or numbers, defects in innate immunity, complement deficiencies, and phenocopies of inborn errors of immunity (Picard et al. 2018. PubMed ID: 29226302; Bousfiha et al. 2018. PubMed ID: 29226301; Tangye et al. 2020. PubMed ID: 31953710). Overall, PIDs are associated with an increased susceptibility to infectious disease, autoimmunity, autoinflammatory diseases, allergy, and/or malignancy (Tangye et al. 2020. PubMed ID: 31953710). However, many PIDs have overlapping symptoms making diagnosis challenging. Different therapeutics may be utilized to manage the various diseases (Griffith et al. 2016. PubMed ID: 27262745). Many acquired or secondary PIDs can be caused by malnutrition, infections, environmental stress, drugs, surgery or trauma.

Of note, a PID classification phone app that is based on the International Union of Immunological Societies committee report is available for use (PID Phenotypical Diagnosis App). This app allows one to explore the various PIDs by searching classification tables, specific PIDs, or clinical manifestations.

PGmax™ - Primary Immunodeficiency and Malignancy Predisposition Panel

Primary immunodeficiencies (PID), or inborn errors of immunity, are a heterogenous group of disorders with an incidence of ~1 in 1,000 to 1 in 5,000 births (Griffith et al. 2016. PubMed ID: 27262745; Tangye et al. 2020. PubMed ID: 31953710). There are currently over 400 different PIDs that range in phenotypic severity and age of onset. PIDs encompass a variety of different disorder subclasses including antibody deficiencies, autoinflammatory disorders, combined immunodeficiencies, diseases of immune dysregulation, congenital defects in phagocyte function or numbers, defects in innate immunity, complement deficiencies, and phenocopies of inborn errors of immunity (Picard et al. 2018. PubMed ID: 29226302; Bousfiha et al. 2018. PubMed ID: 29226301; Tangye et al. 2020. PubMed ID: 31953710). Overall, PIDs are associated with an increased susceptibility to infectious disease, autoimmunity, autoinflammatory diseases, allergy, or malignancy (Tangye et al. 2020. PubMed ID: 31953710).

After infections, malignancy in PID patients is the second-highest cause of death in children and adults (Riaz et al. 2019. PubMed ID: 31057537). Some PIDs have a higher susceptibility to malignancy than others, specifically common variable immunodeficiency (CVID), combined immunodeficiencies affecting cellular immunity (especially DNA repair defects), or those that impair immune regulatory control (Riaz et al. 2019. PubMed ID: 31057537). Data from the United States Immune Deficiency Network (USIDNET) registry identified a 1.42-fold excess relative risk of cancer in individuals with PID as compared to age-adjusted controls (Mayor et al. 2018. PubMed ID: 28606585). There was a significant increase in lymphoma in both men and women with PID, while there was no significant increase in the incidence of lung, color, breast, or prostate cancers in the PID patients. 

Lymphoid malignancies are cancers that originate from cells of the immune system, lymphocytes. These malignancies may include non-Hodgkin lymphoma, Hodgkin lymphoma, myeloma, and lymphocytic leukemia. Lymphomas account for two-thirds of all malignancies reported in PID patients (Filipovich et al. 1992. PubMed ID: 1327508; Mayor et al. 2018. PubMed ID: 28606585) and more in individuals with either combined immunodeficiency, DNA repair defects, or antibody deficiencies (Filipovich et al. 1992. PubMed ID: 1327508; Vajdic et al. 2010. PubMed ID: 20466855; Riaz et al. 2019. PubMed ID: 31057537). Most lymphomas reported in relation to PID are B cell lymphomas; however, T cell lymphomas have been reported in a few studies and are generally associated with chromosomal breakage disorders or cartilage hair hypoplasia (Riaz et al. 2019. PubMed ID: 31057537). There may be a higher prevalence of T cell lymphoma in patients with secondary immunodeficiencies; however, this finding may be a result of treatment bias (Nijland et al. 2018. PubMed ID: 29269521). Due to poor prognosis and complex therapeutics approaches, the management of lymphoma in patients with a PID is difficult (Herber et al. 2020. PubMed ID: 31580160).

PGmax™ - Inborn Errors of Immunity/Primary Immunodeficiency (PID) Panel

This test includes genes identified through literature, OMIM, and HGMD searches that have a reported association with PIDs. In addition, this panel includes genes associated with a variety of inborn errors of immunity as described by the International Union of Immunological Societies Primary Immunodeficiency Diseases Committee (Picard et al. 2018. PubMed ID: 29226302; Bousfiha et al. 2018. PubMed ID: 29226301; Tangye et al. 2020. PubMed ID: 31953710).

Inborn errors of immunity are genetically heterogeneous disorders. Disorders may be inherited in an autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) manner, or may arise de novo. Causative variants may include missense, nonsense, splicing, regulatory, or copy number alterations.

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

PGmax™ - Primary Immunodeficiency and Malignancy Predisposition Panel

This test includes genes identified through literature, OMIM, and HGMD searches that have a reported association with PIDs and lymphoid malignancy predisposition. In addition, this panel includes genes associated with a variety of inborn errors of immunity as described by the International Union of Immunological Societies Primary Immunodeficiency Diseases Committee are also included (Picard et al. 2018. PubMed ID: 29226302; Bousfiha et al. 2020. PubMed ID: 32048120; Tangye et al. 2020. PubMed ID: 31953710).

Disorders leading to immunodeficiency and a lymphoid malignancy predisposition are genetically heterogeneous disorders. Disorders may be inherited in an autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) manner or may arise de novo. Causative variants may include missense, nonsense, splicing, regulatory, or copy number alterations.

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

PGmax™ - Inborn Errors of Immunity/Primary Immunodeficiency (PID) Panel

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 97.8% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Due to the complexity of the region, there is limited coverage for the following genes: F8, GPIBA, IKBKG, PI4KA, RANBP2, RPS17, and UPS18.

The report will include pathogenic and likely pathogenic variants that may not be related to the patient's phenotype, but may indicate carrier status for an autosomal recessive disorder or a predisposition for an autosomal dominant disorder included on the panel. However, the report will not include all the observed rare variants of uncertain significance due to the large number of genes included in this panel. Variants of uncertain significance and risk variants that are considered to contribute to the patient's phenotype will be reported. CNVs that are found to encompass all or part of a gene(s) that is known or possibly associated with the patient’s phenotype will also be reported. A list of all rare variants included in this panel is available along with our interpretations upon request.

Reports will consist of two different sections:

• Variants in genes known to be associated with the provided phenotype
• Variants in genes possibly associated with the provided phenotype

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

PGmax™ - Primary Immunodeficiency and Malignancy Predisposition Panel

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 97.8% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Due to the complexity of the region, there is limited coverage for the following genes: DDX11, F8, GP1BA, IKBKG, PI4KA, RANBP2, RPS17, and UPS18.

The report will include pathogenic and likely pathogenic variants that may not be related to the patient's phenotype, but may indicate carrier status for an autosomal recessive disorder or a predisposition for an autosomal dominant disorder included on the panel. However, the report will not include all the observed rare variants of uncertain significance due to the large number of genes included in this panel. Variants of uncertain significance and risk variants that are considered to contribute to the patient's phenotype will be reported. CNVs that are found to encompass all or part of a gene(s) that is known or possibly associated with the patient’s phenotype will also be reported. A list of all rare variants included in this panel is available along with our interpretations upon request.

Reports will consist of two different sections:

• Variants in genes known to be associated with the provided phenotype

• Variants in genes possibly associated with the provided phenotype

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

The patient must reside in the United States, Puerto Rico, or Canada and meet two or more of the following criteria, unless otherwise specified:

Clinical Features

• Bronchiectasis
• Lymphadenopathy for greater than one month
• Chronic hepatomegaly or chronic splenomegaly
• Severe, persistent, or recurrent Herpesviridae infections (e.g., EBV, cytomegalovirus)
• Enteropathy
• Lymphoma at 0-25 years - meets the 2 eligibility criteria
• Lymphoma at ≥ 26 years of age - requires second eligibility criteria

Laboratory

• Elevated levels of immunoglobulin M
• Increased number of follicular helper T cells
• Reduced number of naïve B cells

History

• Common Variable Immune Deficiency (CVID) phenotype or direct family member with CVID phenotype
• Relative with PIK3CD or PIK3R1 genotype (first or second degree) - meets the 2 eligibility criteria

Individuals tested through this program are eligible for pre- and/or post-test genetic counseling to help them understand genetic testing and their test results. This service is provided through Genome Medical, a third-party genetic counseling service, and is made available by Pharming Healthcare Inc. at no-charge as part of the program. Patients can access genetic counseling by having their healthcare provider complete the pre- and/or post-test genetic counseling section of the PreventionGenetics test requisition form.

Patients will receive an email and/or text message from Genome Medical with a link to schedule their genetic counseling appointment. Appointments are typically available within 1-3 days.

SPECIMEN REQUIREMENTS

Whole Blood

Collect 3 ml - 5 ml of whole blood in EDTA (purple top tube) or ACD (yellow top tube), minimum 1 ml for small infants. Specimens may be refrigerated and/or shipped at room temperature.

Saliva

Oragene™ or GeneFiX™ Saliva Collection kit used according to manufacturer instructions. DNA from saliva specimens is invariably contaminated with microbial and food DNA, which can impact specimen quality and may result in delayed testing and/or the need for a second specimen. Specimens may be shipped at room temperature.

OCD-100 Buccal Swab

OCD-100 Buccal Swab used according to manufacturer instructions. Specimens may be shipped at room temperature.

SHIPPING AND HANDLING INSTRUCTIONS

Label all specimen containers with the patient's name, date of birth, and/or ID number. At least two identifiers should be listed on specimen containers. Specimen deliveries are accepted Monday-Saturday for all specimen types. Holiday schedules will be posted on our website at least one week prior to major holidays.