Primary Immunodeficiency (PID) and Primary Ciliary Dyskinesia (PCD) Panel

Last modified: Sep 03, 2018

Summary

  • Is a 308 gene panel that includes assessment of non-coding variants
  • Panel is ideal for patients with a clinical suspicion of primary immunodeficiency (PID), especially, if primary ciliary dyskinesia (PCD) is considered important for differential diagnostics.

Analysis methods

  • FLEX
  • PLUS
  • SEQ
  • DEL/DUP

Availability

3-4 weeks

Number of genes

308

Test code

IM0801

CPT codes

SEQ 81404
SEQ 81406
SEQ 81408
DEL/DUP 81479

Summary

The Blueprint Genetics Primary Immunodeficiency (PID) and Primary Ciliary Dyskinesia (PCD) Panel (test code IM0801):

  • Is a 308 gene panel that includes assessment of selected non-coding disease-causing variants
  • Is available as PLUS analysis (sequencing analysis and deletion/duplication analysis), sequencing analysis only or deletion/duplication analysis only

ICD codes

Commonly used ICD-10 code(s) when ordering the Primary Immunodeficiency (PID) and Primary Ciliary Dyskinesia (PCD) Panel

ICD-10 Disease
Q34.8 Primary ciliary dyskinesia
Q34.8 Other specified congenital malformations of respiratory system
E84.0 Cystic fibrosis
E84.19 Cystic fibrosis
E84.8 Cystic fibrosis
E84.9 Cystic fibrosis
N46.8 Infertility
D80.9 Immunodeficiencies with antibody defects
D81.9 Combined immunodeficiencies

Sample Requirements

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

Subpanel description

This comprehensive Panel includes the following panels: Severe Combined Immunodeficiency Panel, Dyskeratosis Congenita Panel, Autoinflammatory Syndrome Panel, Congenital Neutropenia Panel, Chronic Granulomatous Disease Panel and Primary Ciliary Dyskinesia Panel.

Primary immunodeficiencies (PIDs) are a genetically heterogeneous group of diseases. The International Union of Immunological Societies Expert Committee categorizes PIDs into nine different categories: 1) combined immunodeficiencies, 2) combined immunodeficiencies with associated or syndromic features, 3) predominantly antibody deficiencies, 4) diseases of immune dysregulation, 5) congenital defects of phagocyte number, function, or both, 6) defects in intrinsic and innate immunity, 7) autoinflammatory disorders, 8) complement deficiencies and 9) phenocopies of PIDs. Despite a heterogeneous genetic basis, the core symptoms are often very similar and can complicate the diagnosis. In addition, many PIDs may be included in more than one category. Without knowing the specific mutation in the causative gene, treatment choice can be a complicated process. Also, type and site of and specific organisms causing the infections may help to classify the disease. In addition to immune-related symptoms, many PIDs have non-immune manifestations. The prevalence of individual PIDs have a wide range, but the combined prevalence of all primary immunodeficiencies is reported to be as high as 5-8:10,000. Some recently identified PIDs are extremely rare.

Primary ciliary dyskinesia (PCD) is a disorder characterized by chronic respiratory tract infections, situs abnormalities (situs ambiguous and situs inversus), and sometimes infertility due to abnormal sperm motility. The signs and symptoms of this condition are caused by abnormal cilia. Affected patients may have signs of PCD at birth or within the first few months of life; however, the symptoms and disease onset vary depending on the underlying genetic defect. Most full-term neonates have respiratory distress with tachypnea (infant acute respiratory distress syndrome). Typical findings in infants and children include daily rhinitis and daily year-round wet cough occurring soon after birth with associated recurrent or chronic infections of the lower airways. Patients with PCD, especially young children, may also experience recurrent ear infections (otitis media). The prevalence of PCD is difficult to determine. Among population isolates with a high rate of consanguinity, the incidence rate may be especially high. The total number of individuals with PCD in the United States is estimated to be 12,000-17,000. PCD has an estimated incidence of 1:15,000-1:30,000 live births; however, this is probably an underestimate. The Primary Ciliary Dyskinesia Panel includes testing for cystic fibrosis (CF), which is characterized by the production of sweat with a high salt content and mucus secretions with an abnormal viscosity. CF is caused by mutations in the CFTR gene. The disease is chronic and generally progressive, with onset usually occurring during early childhood.

Genes in the Primary Immunodeficiency (PID) and Primary Ciliary Dyskinesia (PCD) Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ACD Dyskeratosis congenita, autosomal dominant 6, Dyskeratosis congenita, autosomal recessive 7 AD/AR 2 8
ACP5 Spondyloenchondrodysplasia with immune dysregulation AR 11 26
ACTB* Baraitser-Winter syndrome AD 46 54
ADA Severe combined immunodeficiency due to adenosine deaminase deficiency AR 39 88
ADAM17 Inflammatory skin and bowel disease, neonatal 1 AR 1 5
ADAR Dyschromatosis symmetrica hereditaria, Aicardi-Goutières syndrome AD/AR 24 211
AICDA Immunodeficiency with hyper-IgM AD/AR 14 50
AIRE Autoimmune polyendocrinopathy syndrome AD/AR 52 133
AK2 Reticular dysgenesis AR 14 17
AP3B1 Hermansky-Pudlak syndrome AR 14 31
ARMC4* Ciliary dyskinesia AR 14 16
ARPC1B Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease AR 2 4
ATM Breast cancer, Ataxia-Telangiectasia AD/AR 860 1026
BACH2 BACH2-related immunodeficiency and autoimmunity (BRIDA) AD 2
BCL10 Immunodeficiency 37 AR 16 1
BCL11B Immunodeficiency 49 AD 3 1
BLM Bloom syndrome AR 91 107
BLNK Agammaglobulinemia 4 AR 1 3
BTK Hypogammaglobulinemia, Agammaglobulinemia and isolated hormone deficiency, Agammaglobulinemia XL 108 900
C1QA C1q deficiency AR 2 7
C1QB C1q deficiency AR 4 7
C1QC C1q deficiency AR 4 7
C1S Complement component C1s deficiency AR 4 9
C2* Complement component 2 deficiency AR 4 9
C3 Hemolytic uremic syndrome, atypical, Complement component 3 deficiency, Macular degeneration, age-related AD/AR 6 82
C21ORF59 Ciliary dyskinesia AR 3 4
CARD9 Candidiasis, familial, 2 AR 5 24
CARD11 B-cell expansion with NFKB and T-cell anergy, Immunodeficiency AD/AR 11 8
CARD14 Psoriasis AD 9 26
CASP8 Caspase 8 defiency AR 2 4
CASP10 Autoimmune lymphoproliferative syndrome AD 5 7
CCDC39 Ciliary dyskinesia AR 25 38
CCDC40 Ciliary dyskinesia AR 24 33
CCDC65 Ciliary dyskinesia AR 2 1
CCDC103 Ciliary dyskinesia AR 4 4
CCDC114 Ciliary dyskinesia AR 6 7
CCNO Ciliary dyskinesia AR 9 9
CD3D Immunodeficiency AR 3 5
CD3E Immunodeficiency AR 3 7
CD3G Immunodeficiency AR 3 3
CD8A CD8 deficiency AR 1 1
CD19 Immunodeficiency, common variable AR 8 9
CD27 Lymphoproliferative syndrome AR 2 8
CD40 Immunodeficiency with Hyper-IgM AR 5 9
CD40LG Immunodeficiency, with hyper-IgM XL 31 227
CD46* Hemolytic uremic syndrome, atypical AD/AR 5 69
CD55 Blood group, Cromer system BG 7 6
CD59 CD59 deficiency AR 4 7
CD70 Primary immunodeficiency AR 3
CD79A Agammaglobulinemia 3 AR 2 6
CD79B Agammaglobulinemia 6 AR 2 3
CD81 Immunodeficiency, common variable, 6 AR 1 1
CD247 Immunodeficiency AR 7 4
CDCA7 Immunodeficiency-centromeric instability-facial anomalies syndrome 3 AR 4 6
CEBPE Specific granule deficiency 1 AR 2 4
CECR1 Polyarteritis nodosa, ADA2 deficiency AR 14 45
CENPF Ciliary dyskinesia -Lethal Ciliopathy AR 12 7
CFB Complement factor B deficiency, Hemolytic uremic syndrome, atypical AD/AR 2 21
CFD Complement factor D deficiency AR 2 3
CFH* Hemolytic uremic syndrome, atypical, Complement factor H deficiency, Basal laminar drusen AD/AR 18 269
CFI Hemolytic uremic syndrome, atypical, Complement factor I deficiency AD/AR 9 139
CFP Properdin deficiency XL 5 17
CFTR Cystic fibrosis, Congenital bilateral absence of the vas deferens AR 465 1790
CHD7 Isolated gonadotropin-releasing hormone deficiency, CHARGE syndrome AD 244 813
CIITA Bare lymphocyte syndrome AR 8 14
CLCN7 Osteopetrosis AD/AR 13 95
CLPB 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MEGCANN) AR 25 25
COLEC11 3MC syndrome AR 6 9
COPA Autoimmune interstitial lung, joint, and kidney disease AD 5 6
CORO1A* Immunodeficiency AR 39 6
CR2 Common variable immunodeficiency AR 2 9
CSF2RA* Surfactant metabolism dysfunction, pulmonary XL 2 17
CSF2RB Surfactant metabolism dysfunction, pulmonary, 5 AR 2 5
CSF3R Neutrophilia, hereditary AD 10 10
CTC1 Cerebroretinal microangiopathy with calcifications and cysts AR 16 30
CTLA4 Autoimmune lymphoproliferative syndrome, type V AD 12 27
CTPS1 Immunodeficiency 24 AR 1 1
CTSC Periodontitis, juvenile, Haim-Munk syndrome, Papillon-Lefevre syndrome AR 16 92
CXCR4 Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome AD 5 15
CYBA Chronic granulomatous disease AR 12 67
CYBB Chronic granulomatous disease, Immunodeficiency XL 63 750
DCLRE1C* Omenn syndrome, Severe combined immunodeficiency with sensitivity to ionizing radiation AR 17 83
DDX58 Singleton-Merten syndrome AD 4 2
DGKE Nephrotic syndrome AR 16 27
DKC1 Hoyeraal-Hreidarsson syndrome, Dyskeratosis congenita XL 47 71
DNAAF1 Ciliary dyskinesia AR 14 31
DNAAF2 Ciliary dyskinesia AR 11 4
DNAAF3 Primary ciliary dyskinesia AD/AR 8 3
DNAAF5 Ciliary dyskinesia AR 8 2
DNAH1 Spermatogenic failure 18 AR 10 25
DNAH5 Ciliary dyskinesia AR 95 160
DNAH11* Ciliary dyskinesia AR 51 101
DNAI1 Ciliary dyskinesia AR 14 29
DNAI2 Ciliary dyskinesia AR 14 6
DNAJC21 Bone marrow failure syndrome 3 AR 5 8
DNAL1 Ciliary dyskinesia AR 3 1
DNMT3B Immunodeficiency-centromeric instability-facial anomalies syndrome AR 14 50
DOCK2 Immunodeficiency AR 5 6
DOCK8 Hyper-IgE recurrent infection syndrome, Mental retardation, autosomal dominant 2 AR 38 162
DRC1 Primary ciliary dyskinesia AD/AR 4 2
DYX1C1 Ciliary dyskinesia AR 11 11
ELANE Neutropenia AD 38 215
EPG5 Vici syndrome AR 29 50
ERCC6L2 Bone marrow failure syndrome 2 AR 4 2
EXTL3 Immunoskeletal dysplasia with neurodevelopmental abnormalities (ISDNA) AR 4 7
FADD Infections, recurrent, with encephalopathy, hepatic dysfunction, and cardiovascular malformations AR 2 1
FAS Autoimmune lymphoproliferative syndrome AD/AR 28 131
FASLG Autoimmune lymphoproliferative syndrome, type IB AD 3 9
FERMT3 Leukocyte adhesion deficiency AR 8 14
FOXN1 T-cell immunodeficiency, congenital alopecia, and nail dystrophy AR 4 6
FOXP3 Immunodysregulation, polyendocrinopathy, and enteropathy XL 25 81
G6PC3 Neutropenia, severe congenital, Dursun syndrome AR 12 37
G6PD Glucose-6-phosphate dehydrogenase deficiency XL 42 222
GAS8 Ciliary dyskinesia, primary, 33 AR 4 6
GATA2 Myelodysplastic syndrome, Chronic neutropenia associated with monocytopenia, evolving to myelodysplasia and acute myeloid leukemia, Acute myeloid leukemia, Emberger syndrome, Immunodeficiency AD 26 105
GFI1 Neutropenia, severe congenital, 2 autosomal dominant, Neutropenia, nonimmune chronic idiopathic, of adults AD 2 5
GINS1 Immunodeficiency AR 4 4
HAX1 Neutropenia, severe congenital AR 9 19
HELLS Immunodeficiency-centromeric instability-facial anomalies syndrome 4 AR 6 6
HYDIN*,# Primary ciliary dyskinesia AD/AR 5 15
HYOU1 Combined immunodeficiency AR 2
ICOS Immunodeficiency, common variable, 1 AR 2 4
IFIH1 Singleton-Merten syndrome, Aicardi-Goutieres syndrome 7 AD 13 17
IFNAR2 Immunodeficiency 45 AR 1 2
IFNGR1 Immunodeficiency AD/AR 16 40
IFNGR2 Immunodeficiency AR 4 18
IGLL1* Agammaglobulinemia AR 2 2
IKBKB Immunodeficiency 15 AR 2 6
IKZF1# Immunodeficiency, common variable, 13 AD 7 12
IL1RN Osteomyelitis, sterile multifocal, with periostitis and pustulosis AR 6 13
IL2RA Interleukin 2 receptor, alpha, deficiency AR 6 6
IL2RG Combined immunodeficiency XL 52 220
IL7R Severe combined immunodeficiency, , T-cell negative, B-cell positive, NK cell positive AR 20 47
IL10 Graft vs. host disease AD 1 3
IL10RA Inflammatory bowel disease AR 4 37
IL10RB Inflammatory bowel disease AR 2 17
IL12B Immunodeficiency 28, Immunodeficiency 29 AR 3 13
IL12RB1 Immunodeficiency AR 10 82
IL17RA Immunodeficiency 51 AR 6 15
IL17RC Candiasis, familial, 9 AR 4 3
IL21 Immunodeficiency, common variable, 11 AR 1 1
IL21R Immunodeficiency, primary, autosomal recessive, IL21R-related AR 3 9
IL36RN Pustular psoriasis, generalized AR 6 23
INVS Nephronophthisis AR 12 33
IRAK4 IRAK4 deficiency, Invasive pneumococcal disease, recurrent, isolated, 1 AR 10 29
IRF2BP2 Immunodeficiency, common variable, 14 AD 1 1
IRF8 Immunodeficiency 32A (CD11C-positive/CD1C-positive dendritic cell deficiency), Immunodeficiency 32B (monocyte and dendritic cell deficiency) AD 3 6
ISG15 Immunodeficiency, with basal ganglia calcification AR 3 3
ITGB2 Leukocyte adhesion deficiency AR 33 114
ITK Lymphoproliferative syndrome AR 4 10
JAGN1 Neutropenia, severe congenital AR 8 8
JAK1 Primary immunodeficiency AR 4 4
JAK3 Severe combined immunodeficiency, , T cell-negative, B cell-positive, natural killer cell-negative AR 27 63
KRAS* Noonan syndrome, Cardiofaciocutaneous syndrome AD 61 34
LAMTOR2 Immunodeficiency due to defect in MAPBP-interacting protein AR 1 1
LAT Immunodeficiency 52 AR 2 18
LCK Immunodeficiency AR 2 3
LIG4 Severe combined immunodeficiency with sensitivity to ionizing radiation, LIG4 syndrome AR 16 35
LPIN2 Majeed syndrome AR 9 12
LRBA Common variable immunodeficiency AR 19 60
LRRC6 Ciliary dyskinesia AR 7 17
LYST* Chediak-Higashi syndrome AR 46 87
MAGT1 Immunodeficiency, with magnesium defect, Epstein-Barr virus infection and neoplasia, Mental retardation, X-linked 95 XL 5 14
MALT1 Immunodeficiency AR 3 5
MAP3K14 Primary immunodeficiency with multifaceted aberrant lymphoid immunity AR 1 1
MASP1 3MC syndrome AR 8 19
MEFV Familial Mediterranean fever AD/AR 27 178
MKL1 Primary immunodeficiency AR 3
MOGS Congenital disorder of glycosylation AR 6 6
MRE11A Ataxia-telangiectasia-like disorder-1 AR 57 51
MSN* Immunodeficiency 50 XL 2 2
MTHFD1 Severe combined immunodeficiency AR 9 9
MVK Mevalonic aciduria, Hyper-IgD syndrome, Porokeratosis 3, multiple types AR 30 180
MYD88 MYD88 deficiency AR 6 5
MYO5A Griscelli syndrome AR 5 6
NBN Breast cancer, Nijmegen breakage syndrome AD/AR 141 87
NCF1*,# Chronic granulomatous disease AR 18 38
NCF2 Chronic granulomatous disease AR 13 64
NCF4 Granulomatous disease AR 4 2
NCSTN Acne inversa, familial 1 AD 6 29
NFKB1 Common variable immunodeficiency AD 8 12
NFKB2 Common variable immunodeficiency AD 6 11
NFKBIA Ectodermal dysplasia, anhidrotic, with T-cell immunodeficiency AD 5 10
NHEJ1 Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation AR 14 15
NHP2 Dyskeratosis congenita AR 3 3
NLRC4 Autoinflammation with infantile enterocolitis (AIFEC), Familial cold autoinflammatory syndrome 4 AD 6 7
NLRP1 Palmoplantar carcinoma, multiple self-healing, Autoinflammation with arthritis and dyskeratosis AD 6 15
NLRP3 Neonatal onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome, Chronic infantile neurologic cutaneous articular (CINCA) syndrome, Familial cold-induced autoinflammatory syndrome 1 AD 22 129
NLRP12 Familial cold autoinflammatory syndrome AD 3 11
NME8 Ciliary dyskinesia AR 1 5
NOD2 Blau syndrome, Sarcoidosis, early-onset AD/AR 12 63
NOP10 Dyskeratosis congenita AR 1 1
NRAS Noonan syndrome AD 31 14
NSMCE3 Lung disease, immunodeficiency, and chromosome breakage syndrome (LICS) AR 2 2
OFD1 Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital syndrome, Joubert syndrome XL 142 157
ORAI1 Immunodeficiency, Myopathy, tubular aggregate, 2 AR 9 13
OTULIN Autoinflammation, panniculitis, and dermatosis syndrome (AIPDS) AR 7 3
PARN* Pulmonary fibrosis and/or bone marrow failure, Dyskeratosis congenita AD/AR 15 24
PEPD Prolidase deficiency AR 12 30
PGM3 Immunodeficiency 23 AR 13 14
PIGA* Multiple congenital anomalies-hypotonia-seizures syndrome XL 24 24
PIH1D3# Ciliary dyskinesia, primary, 36 XL 2 11
PIK3CD* Immunodeficiency AD 5 11
PIK3R1 Agammaglobulinemia, SHORT syndrome AD/AR 32 23
PLCG2 Familial cold autoinflammatory syndrome 3 (PLAID), Autoinflammation, antibody deficiency, and immune dysregulation syndrome (APLAID) AD 7 9
PMS2* Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposis AD/AR 259 324
PNP Purine nucleoside phosphorylase deficiency AR 11 33
POLE Colorectal cancer, Facial dysmorphism, immunodeficiency, livedo, and short stature syndrome (FILS syndrome) AD/AR 7 50
POLE2 Combined immunodeficiency AR 3
PRF1 Lymphoma, non-Hodgkin, Aplastic anemia, adult-onset, Hemophagocytic lymphohistiocytosis AR 22 172
PRKCD Autoimmune lymphoproliferative syndrome type III AR 3 5
PRKDC Immunodeficiency AR 6 7
PSENEN Acne inversa, familial, 2 AD 7 15
PSMB8 Nakajo-Nishimura syndrome, Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome, Autoinflammation, lipodystrophy, and dermatosis syndrome, Joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome AR 4 9
PSTPIP1 Pyogenic sterile arthritis, pyoderma gangrenosum, and acne AD 5 28
PTPRC Severe combined immunodeficiency, , T-cell negative, B-cell positive, NK cell positive AR 4 5
RAB27A Griscelli syndrome, Elejalde syndrome AR 17 53
RAC2 Neutrophil immunodeficiency syndrome AD 2 3
RAG1 Omenn syndrome, Alpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severe cytomegalovirus infection, and autoimmunity, T cell-negative, B cell-negative, natural killer cell-positive severe combined immunodeficiency, Combined cellular and humoral immune defects with granulomas AR 48 182
RAG2 Omenn syndrome, Combined cellular and humoral immune defects with granulomas AR 26 79
RASGRP1 Primary immunodeficiency AR 1 1
RBCK1 Polyglucosan body myopathy AR 10 14
RECQL4 Baller-Gerold syndrome, RAPADILINO syndrome, Rothmund-Thomson syndrome AR 53 100
RFX5 Bare lymphocyte syndrome AR 5 6
RFXANK MHC class II deficiency AR 6 14
RFXAP Bare lymphocyte syndrome AR 5 7
RHOH T-cell immunodeficiency with epidermodysplasia verruciformis AD/AR 1
RLTPR Combined immunodeficiency AR 3 5
RMRP Cartilage-hair hypoplasia, Metaphyseal dysplasia without hypotrichosis, Anauxetic dysplasia AR 34 123
RNASEH2A Aicardi-Goutières syndrome AR 13 21
RNASEH2B Aicardi-Goutières syndrome AR 13 40
RNASEH2C Aicardi-Goutières syndrome AR 6 14
RNF31 HOIP and LUBAC deficiency AR 1
RNF168 RIDDLE syndrome AR 4 4
RNU4ATAC Roifman syndrome, Microcephalic osteodysplastic primordial dwarfism type 1, Microcephalic osteodysplastic primordial dwarfism type 3 AR 15 21
RORC Immunodeficiency 42 AR 3 3
RPGR Retinitis pigmentosa, Cone-rod dystrophy, X-linked, 1, Macular degeneration, X-linked atrophic, Retinitis pigmentosa 3 XL 69 203
RPSA Asplenia, isolated congenital AD 7 8
RSPH1 Ciliary dyskinesia AR 13 10
RSPH3 Ciliary dyskinesia, primary, 32 AR 6 5
RSPH4A Ciliary dyskinesia AR 12 24
RSPH9 Ciliary dyskinesia AR 6 11
RTEL1 Pulmonary fibrosis and/or bone marrow failure, Dyskeratosis congenita AD/AR 33 45
SAMD9 Mirage syndrome, Tumoral calcinosis, normophosphatemic AR 7 17
SAMD9L Ataxia-pancytopenia syndrome AD 4 4
SAMHD1 Aicardi-Goutières syndrome, Chilblain lupus 2 AR 23 55
SBDS* Aplastic anemia, Shwachman-Diamond syndrome, Severe spondylometaphyseal dysplasia AD/AR 21 90
SERPING1 Angioedema, Complement component 4, partial deficiency of AD/AR 33 536
SH2D1A Lymphoproliferative syndrome XL 15 126
SLC7A7 Lysinuric protein intolerance AR 52 66
SLC29A3 Histiocytosis-lymphadenopathy plus syndrome, Dysosteosclerosis AR 16 24
SLC35C1 Congenital disorder of glycosylation, Leukocyte adhesion deficiency AR 6 7
SLC37A4 Glycogen storage disease AR 29 109
SLC46A1 Folate malabsorption AR 17 20
SMARCAL1 Schimke immunoosseous dysplasia AR 17 88
SMARCD2 Specific granule defiency 2 AR 3 1
SP110 Hepatic venoocclusive disease with immunodeficiency AR 7 7
SPAG1 Primary ciliary dyskinesia AD/AR 16 10
SPINK5 Netherton syndrome AR 23 83
SRP72* Bone marrow failure syndrome 1 AD 2 2
STAT1 Immunodeficiency AD/AR 34 117
STAT2 Immunodeficiency AR 2 6
STAT3 Hyper-IgE recurrent infection syndrome, Autoimmune disease, multisystem, infantile onset AD 44 147
STAT5B* Growth hormone insensitivity with immunodeficiency AR 8 10
STIM1 Stormorken syndrome, Immunodeficiency, Myopathy, tubular aggregate 1 AD/AR 12 22
STK4 T-cell immunodeficiency syndrome, recurrent infections, autoimmunity, AR 3 7
STX11 Hemophagocytic lymphohistiocytosis, familial AR 6 18
STXBP2 Hemophagocytic lymphohistiocytosis, familial AR 9 69
TAP1 Bare lymphocyte syndrome AR 1 7
TAP2 Bare lymphocyte syndrome AR 2 8
TAPBP Bare lymphocyte syndrome AR 1 2
TBX1 Conotruncal anomaly face syndrome AD 15 65
TCF3 Agammaglobulinemia 8, autosomal dominant AD 1 4
TCN2 Transcobalamin II deficiency AR 9 33
TERC Aplastic anemia, Pulmonary fibrosis and/or bone marrow failure, telomere-related, Dyskeratosis congenita AD 38 67
TERT Aplastic anemia, Pulmonary fibrosis and/or bone marrow failure, telomere-related, Dyskeratosis congenita AD/AR 43 152
TFRC Immunodeficiency 46 AR 8 1
THBD Thrombophilia due to thrombomodulin defect, Hemolytic uremic syndrome, atypical AD 5 22
TINF2 Revesz syndrome, Dyskeratosis congenita AD 23 37
TMC6 Epidermodysplasia verruciformis AR 5 7
TMC8 Epidermodysplasia verruciformis AR 3 9
TMEM173 STING-associated vasculopathy, infantile-onsent (SAVI) AD 3 10
TNFAIP3 Autoinflammatory syndrome, familial, Behcet-like AD 8 12
TNFRSF1A Periodic fever (TNF receptor-associated periodic syndrome) AD 20 104
TNFRSF4 Immunodeficiency AR 1 1
TNFRSF13B Common variable immunodeficiency, Immunoglobulin A deficiency AD/AR 6 48
TRAF3IP2 Candidiasis, familial 8 AR 1 3
TREX1 Vasculopathy, retinal, with cerebral leukodystrophy, Chilblain lupus, Aicardi-Goutières syndrome AD/AR 30 68
TRNT1 Retinitis pigmentosa and erythrocytic microcytosis AR 13 26
TTC7A Gastrointestinal defects and immunodeficiency syndrome AR 19 44
TYK2 Immunodeficiency AR 8 8
UNC13D Hemophagocytic lymphohistiocytosis, familial AR 15 156
UNC93B1* Herpes simplex encephalitis, susceptibility to, 1 AR 2
UNC119 Immunodeficiency, Cone-rod dystrophy 2 AR 1 5
UNG Immunodeficiency with hyper-IgM, type 5 AD 4 7
USB1 Poikiloderma with neutropenia AR 23 22
USP18* Pseudo-TORCH syndrome 2 AR 34 1
VPS13B Cohen syndrome AR 248 199
VPS45 Neutropenia, severe congenital, 5, autosomal recessive AR 3 4
WAS Neutropenia, severe congenital, Thrombocytopenia, Wiskott-Aldrich syndrome XL 53 435
WDR1 AR 8
WIPF1 Wiskott-Aldrich syndrome 2 AR 2 2
WRAP53 Dyskeratosis congenita AR 7 5
XIAP* Lymphoproliferative syndrome XL 9 83
ZAP70 Selective T-cell defect AR 14 26
ZBTB24 Immunodeficiency-Centromeric Instability-Facial Anomalies 2 AR 7 17
ZMYND10 Ciliary dyskinesia AR 7 16
ZNF341* AR

* Some, or all, of the gene is duplicated in the genome. Read more.

# The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads).

The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#)

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Orphanet databases.

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number
ADA Chr20:43248503 c.1079-15T>A NM_000022.2 rs387906268
ADA Chr20:43249076 c.976-34G>A NM_000022.2
ATM Chr11:108093770 c.-174A>G NM_000051.3
ATM Chr11:108098321 c.-30-1G>T NM_000051.3 rs869312754
ATM Chr11:108094508 c.-31+595G>A NM_000051.3
ATM Chr11:108121024 c.1236-404C>T NM_000051.3
ATM Chr11:108138753 c.2639-384A>G NM_000051.3
ATM Chr11:108141209 c.2839-579_2839-576delAAGT NM_000051.3
ATM Chr11:108151710 c.3403-12T>A NM_000051.3 rs201370733
ATM Chr11:108158168 c.3994-159A>G NM_000051.3 rs864622543
ATM Chr11:108179837 c.5763-1050A>G NM_000051.3 rs774925473
BTK ChrX:100641212 c.-193A>G NM_000061.2
BTK ChrX:100641049 c.-31+1G>A/C NM_000061.2
BTK ChrX:100641045 c.-31+5G>A/C/T NM_000061.2
BTK ChrX:100641044 c.-31+6T>G NM_000061.2
BTK ChrX:100641050 c.-31G>A NM_000061.2
BTK ChrX:100629827 c.142-205A>G NM_000061.2
BTK ChrX:100609705 c.1567-23A>C/G NM_000061.2
BTK ChrX:100629416 c.240+108T>G NM_000061.2
BTK ChrX:100629415 c.240+109C>A NM_000061.2
BTK ChrX:100613695 c.895-11C>A NM_000061.2
C1QB Chr1:22985931 c.-17-2A>C NM_000491.3
CCDC39 Chr3:180367941 c.1167+1248A>G NM_181426.1
CD40LG ChrX:135736517 c.289-15T>A NM_000074.2
CD40LG ChrX:135737600 c.347-915A>T NM_000074.2
CFTR Chr7:117119984 c.-165G>A NM_000492.3 rs145483167
CFTR Chr7:117119900 c.-249G>C NM_000492.3
CFTR Chr7:117120115 c.-34C>T NM_000492.3 rs756314710
CFTR Chr7:117119654 c.-495C>T NM_000492.3 rs397507565
CFTR Chr7:117120064 c.-85C>G NM_000492.3
CFTR Chr7:117199500 c.1393-18G>A NM_000492.3 rs397508199
CFTR Chr7:117227774 c.1585-19T>C NM_000492.3 rs778457306
CFTR Chr7:117218381 c.1585-9412A>G NM_000492.3 rs397508229
CFTR Chr7:117229530 c.1680-877G>T NM_000492.3 rs397508261
CFTR Chr7:117229524 c.1680-883A>G NM_000492.3
CFTR Chr7:117229521 c.1680-886A>G NM_000492.3 rs397508266
CFTR Chr7:117243855 c.2908+19G>C NM_000492.3 rs370683572
CFTR Chr7:117246713 c.2909-15T>G NM_000492.3 rs397508455
CFTR Chr7:117246840 c.2988+33G>T NM_000492.3
CFTR Chr7:117251624 c.3140-11A>G NM_000492.3
CFTR Chr7:117251609 c.3140-26A>G NM_000492.3 rs76151804
CFTR Chr7:117266272 c.3469-1304C>G NM_000492.3
CFTR Chr7:117267864 c.3717+40A>G NM_000492.3 rs397508595
CFTR Chr7:117280015 c.3718-2477C>T NM_000492.3 rs75039782
CFTR Chr7:117282680 c.3873+33A>G NM_000492.3 rs397508622
CFTR Chr7:117288374 c.3874-4522A>G NM_000492.3
CFTR Chr7:117120325 c.53+124T>C NM_000492.3
CHD7 Chr8:61734568 c.2836-15C>G NM_017780.3
CHD7 Chr8:61757794 c.5051-15T>A NM_017780.3
CLCN7 Chr16:1506057 c.916+57A>T NM_001287.5
CTSC Chr11:88070895 c.-55C>A NM_001814.4 rs766114323
CYBB ChrX:37639267 c.-64C>T NM_000397.3
CYBB ChrX:37639266 c.-65C>T NM_000397.3
CYBB ChrX:37639264 c.-67T>C NM_000397.3
CYBB ChrX:37639262 c.-69A>C NM_000397.3
CYBB ChrX:37664248 c.1152-11T>G NM_000397.3
CYBB ChrX:37641330 c.46-11T>G NM_000397.3
CYBB ChrX:37654041 c.483+978G>T NM_000397.3
CYBB ChrX:37656474 c.674+1080A>G NM_000397.3
CYBB ChrX:37656731 c.674+1337T>G NM_000397.3
CYBB ChrX:37657051 c.675-1157A>G NM_000397.3
DCLRE1C Chr10:14966845 c.973-1777G>C NM_001033855.1
DGKE Chr17:54925466 c.888+40A>G NM_003647.2
DKC1 ChrX:153991100 c.-141C>G NM_001363.3
DKC1 ChrX:153991099 c.-142C>G NM_001363.3 rs199422241
DKC1 ChrX:153993704 c.85-15T>C NM_001363.3
DNMT3B Chr20:31395557 c.2421-11G>A NM_006892.3 rs547940069
DOCK8 Chr9:368196 c.1797+61A>C NM_203447.3 rs786205596
DOCK8 Chr9:271626 c.54-1G>T NM_203447.3 rs192864327
DOCK8 Chr9:317028 c.742-15T>G NM_203447.3 rs111627162
DOCK8 Chr9:317025 c.742-18C>G NM_203447.3 rs112373444
FAS Chr10:90770494 c.506-16A>G NM_000043.4
FASLG Chr1:172628081 c.-261T>C NM_000639.1
FOXP3 ChrX:49106919 c.*876A>G NM_014009.3
FOXP3 ChrX:49106917 c.*878A>G NM_014009.3
GATA2 Chr3:128202171 c.1017+532T>A NM_032638.4
GATA2 Chr3:128202131 c.1017+572C>T NM_032638.4
GINS1 Chr20:25388409 c.-48C>G NM_021067.3
GINS1 Chr20:25388397 c.-60A>G NM_021067.3
IL10RB Chr21:34668714 c.*52C>T NM_000628.4
IL2RG ChrX:70327278 c.*308A>G NM_000206.2
IL2RG ChrX:70331494 c.-105C>T NM_000206.2
IL2RG ChrX:70330553 c.270-15A>G NM_000206.2
IL7R Chr5:35867853 c.379+288G>A NM_002185.3
IRAK4 Chr12:44178047 c.1188+520A>G NM_016123.3
ITGB2 Chr21:46321660 c.500-12T>G NM_000211.3
ITGB2 Chr21:46320404 c.742-14C>A NM_000211.3 rs183204825
JAK3 Chr19:17946035 c.1915-11G>A NM_000215.3
JAK3 Chr19:17943239 c.2680+89G>A NM_000215.3
LAMTOR2 Chr1:156028185 c.*23C>A NM_014017.3
MEFV Chr16:3306969 c.-382C>G NM_000243.2
OFD1 ChrX:13773245 c.1130-22_1130-19delAATT NM_003611.2 rs312262865
OFD1 ChrX:13768358 c.935+706A>G NM_003611.2 rs730880283
PARN Chr16:14724045 c.-165+2C>T NM_001134477.2
PNP Chr14:20942914 c.286-18G>A NM_000270.3
PRKDC Chr8:48844056 c.1777-710dupA NM_006904.6 rs760771518
RAG2 Chr11:36619652 c.-28G>C NM_000536.3
RMRP Chr9:35657745 NR_003051.3 rs377349293
RMRP Chr9:35657746 NR_003051.3 rs551655682
RNASEH2B Chr13:51501530 c.65-13G>A NM_024570.3
RPGR ChrX:38160137 c.1059+363G>A NM_001034853.1
RPSA Chr3:39448260 c.-34+5G>C NM_002295.4
SERPING1 Chr11:57365057 c.-161A>G NM_000062.2
SERPING1 Chr11:57365055 c.-163C>T NM_000062.2
SERPING1 Chr11:57365721 c.-22-1G>A NM_000062.2
SERPING1 Chr11:57365720 c.-22-2A>C/G NM_000062.2
SERPING1 Chr11:57381788 c.1250-13G>A NM_000062.2
SERPING1 Chr11:57373471 c.686-12A>G NM_000062.2
SERPING1 Chr11:57373867 c.890-14C>G NM_000062.2
SPINK5 Chr5:147484503 c.1431-12G>A NM_006846.3 rs368134354
SPINK5 Chr5:147491511 c.1820+53G>A NM_006846.3 rs754599628
SPINK5 Chr5:147465956 c.283-12T>A NM_006846.3
TBX1 Chr22:19743735 c.-620A>C NM_080647.1 rs536892777
TBX1 Chr22:19743578 c.-777C>T NM_080647.1
TCN2 Chr22:31011112 c.581-176A>T NM_000355.3
TERC Chr3:169482870 n.-22C>T NR_001566.1
TERC Chr3:169482906 NR_001566.1
TERT Chr5:1295161 c.-57A>C NM_198253.2
THBD Chr20:23030292 c.-151G>T NM_000361.2 rs16984852
THBD Chr20:23030443 c.-302C>A NM_000361.2
TNFRSF1A Chr12:6443045 c.194-14G>A NM_001065.3 rs104895241
TRNT1 Chr3:3188088 c.609-26T>C NM_182916.2
UNC13D Chr17:73839907 c.118-307G>A NM_199242.2
UNC13D Chr17:73839908 c.118-308C>T NM_199242.2
UNC13D Chr17:73827442 c.2448-13G>A NM_199242.2 rs753762300
UNC13D Chr17:73826245 c.2831-13G>A NM_199242.2
ZAP70 Chr2:98354447 c.1624-11G>A NM_001079.3 rs730880318
ZAP70 Chr2:98349927 c.838-80G>A NM_001079.3 rs113994173

Test strength

The strengths of this test include:
  • CAP and ISO-15189 accreditations covering all operations at Blueprint Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
  • CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
  • Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
  • Careful construction of clinically effective and scientifically justified gene panels
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publically available analytic validation demonstrating complete details of test performance
  • ~1,500 non-coding disease causing variants in Blueprint WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification based on modified ACMG variant classification scheme
  • Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
  • Our comprehensive clinical statements

Test limitations

The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: ARMC4 (9), CORO1A (11), HYDIN (6, 8, 12, 18, 20, 21, 23, 26, 27, 31, 35, 37, 45, 47, 50, 52, 57, 58, 64, 70, 75, 78, 82, 83), IKZF1 (4, 6, 7, 8), NCF1 (1, 5, 8, 9, 11), PMS2 (15), USP18 (11). Genes with suboptimal coverage in our assay are marked with number sign (#) and genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk (*) if they overlap with the UCSC pseudogene regions. Gene is considered to have suboptimal coverage when >90% of the gene’s target nucleotides are not covered at >20x with mapping quality score (MQ>20) reads. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Repeat expansion disorders unless specifically mentioned
  • Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).

This test may not reliably detect the following:

  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

The Blueprint Genetics primary immunodeficiency (PID) and primary ciliary dyskinesia (PCD) panel covers classical genes associated with autoinflammatory disorders, combined immunodeficiencies, congenital defects of phagocytes, cystic fibrosis, defects in innate immunity, diseases of immune dysregulation, immunodeficiencies with antibody defects, infertility, other specified congenital malformations of respiratory system, primary ciliary dyskinesia and situs inversus. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient’s phenotype is suggestive of a specific mutation type.

Performance of Blueprint Genetics Whole Exome Sequencing (WES) assay. All individual panels are sliced from WES data.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.65% (412,456/413,893) >99.99%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.94% (17,070/17,608) >99.99%
11-50 bps 99.07% (957/966) >99.99%
Copy number variants (exon level dels/dups)
Clinical samples (small CNVs, n=52)
1 exon level deletion 92.3% (24/26) NA
2 exons level deletion/duplication 100.0% (11/11) NA
3-7 exons level deletion/duplication 93.3% (14/15) NA
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
Simulated CNV detection
2 exons level deletion/duplication 90.98% (7,357/8,086) 99.96%
5 exons level deletion/duplication 98.63% (7,975/8,086) 99.98%
     
The performance presented above reached by WES with the following coverage metrics
     
Mean sequencing depth at exome level 174x
Nucleotides with >20x sequencing coverage (%) 99.4%

Bioinformatics

The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.

Clinical interpretation

We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analyzed at our laboratory allowed us to further develop the industry standard.

The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant at least three times at Blueprint Genetics. Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at Blueprint Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, congress abstracts and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling. For eligible cases, Blueprint Genetics offers a no charge service to investigate the role of reported VUS (VUS Clarification Service).

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.

General resources