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

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

308 gene panel that includes assessment of non-coding variants

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 Availability Number of genes Test code CPT codes
4 weeks 308 GHC0109 SEQ 81404
SEQ 81406
SEQ 81408
DEL/DUP 81479


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.


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.

Panel Content

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

Gene Associated phenotypes Inheritance ClinVar HGMD
ACDDyskeratosis congenita, autosomal dominant 6, Dyskeratosis congenita, autosomal recessive 7AD/AR28
ACP5Spondyloenchondrodysplasia with immune dysregulationAR1126
ACTBBaraitser-Winter syndromeAD4654
ADASevere combined immunodeficiency due to adenosine deaminase deficiencyAR3988
ADAM17Inflammatory skin and bowel disease, neonatal 1AR15
ADARDyschromatosis symmetrica hereditaria, Aicardi-Goutières syndromeAD/AR24211
AICDAImmunodeficiency with hyper-IgMAD/AR1450
AIREAutoimmune polyendocrinopathy syndromeAD/AR52133
AK2Reticular dysgenesisAR1417
AP3B1Hermansky-Pudlak syndromeAR1431
ARMC4Ciliary dyskinesiaAR1416
ARPC1BPlatelet abnormalities with eosinophilia and immune-mediated inflammatory diseaseAR24
ATMBreast cancer, Ataxia-TelangiectasiaAD/AR8601026
BACH2BACH2-related immunodeficiency and autoimmunity (BRIDA)AD2
BCL10Immunodeficiency 37AR161
BCL11BImmunodeficiency 49AD31
BLMBloom syndromeAR91107
BLNKAgammaglobulinemia 4AR13
BTKHypogammaglobulinemia, Agammaglobulinemia and isolated hormone deficiency, AgammaglobulinemiaXL108900
C1QAC1q deficiencyAR27
C1QBC1q deficiencyAR47
C1QCC1q deficiencyAR47
C1SComplement component C1s deficiencyAR49
C2Complement component 2 deficiencyAR49
C3Hemolytic uremic syndrome, atypical, Complement component 3 deficiency, Macular degeneration, age-relatedAD/AR682
C21ORF59Ciliary dyskinesiaAR34
CARD9Candidiasis, familial, 2AR524
CARD11B-cell expansion with NFKB and T-cell anergy, ImmunodeficiencyAD/AR118
CASP8Caspase 8 defiencyAR24
CASP10Autoimmune lymphoproliferative syndromeAD57
CCDC39Ciliary dyskinesiaAR2538
CCDC40Ciliary dyskinesiaAR2433
CCDC65Ciliary dyskinesiaAR21
CCDC103Ciliary dyskinesiaAR44
CCDC114Ciliary dyskinesiaAR67
CCNOCiliary dyskinesiaAR99
CD8ACD8 deficiencyAR11
CD19Immunodeficiency, common variableAR89
CD27Lymphoproliferative syndromeAR28
CD40Immunodeficiency with Hyper-IgMAR59
CD40LGImmunodeficiency, with hyper-IgMXL31227
CD46Hemolytic uremic syndrome, atypicalAD/AR569
CD55Blood group, Cromer systemBG76
CD59CD59 deficiencyAR47
CD70Primary immunodeficiencyAR3
CD79AAgammaglobulinemia 3AR26
CD79BAgammaglobulinemia 6AR23
CD81Immunodeficiency, common variable, 6AR11
CDCA7Immunodeficiency-centromeric instability-facial anomalies syndrome 3AR46
CEBPESpecific granule deficiency 1AR24
CECR1Polyarteritis nodosa, ADA2 deficiencyAR1445
CENPFCiliary dyskinesia -Lethal CiliopathyAR127
CFBComplement factor B deficiency, Hemolytic uremic syndrome, atypicalAD/AR221
CFDComplement factor D deficiencyAR23
CFHHemolytic uremic syndrome, atypical, Complement factor H deficiency, Basal laminar drusenAD/AR18269
CFIHemolytic uremic syndrome, atypical, Complement factor I deficiencyAD/AR9139
CFPProperdin deficiencyXL517
CFTRCystic fibrosis, Congenital bilateral absence of the vas deferensAR4651790
CHD7Isolated gonadotropin-releasing hormone deficiency, CHARGE syndromeAD244813
CIITABare lymphocyte syndromeAR814
CLPB3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MEGCANN)AR2525
COLEC113MC syndromeAR69
COPAAutoimmune interstitial lung, joint, and kidney diseaseAD56
CR2Common variable immunodeficiencyAR29
CSF2RASurfactant metabolism dysfunction, pulmonaryXL217
CSF2RBSurfactant metabolism dysfunction, pulmonary, 5AR25
CSF3RNeutrophilia, hereditaryAD1010
CTC1Cerebroretinal microangiopathy with calcifications and cystsAR1630
CTLA4Autoimmune lymphoproliferative syndrome, type VAD1227
CTPS1Immunodeficiency 24AR11
CTSCPeriodontitis, juvenile, Haim-Munk syndrome, Papillon-Lefevre syndromeAR1692
CXCR4Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndromeAD515
CYBAChronic granulomatous diseaseAR1267
CYBBChronic granulomatous disease, ImmunodeficiencyXL63750
DCLRE1COmenn syndrome, Severe combined immunodeficiency with sensitivity to ionizing radiationAR1783
DDX58Singleton-Merten syndromeAD42
DGKENephrotic syndromeAR1627
DKC1Hoyeraal-Hreidarsson syndrome, Dyskeratosis congenitaXL4771
DNAAF1Ciliary dyskinesiaAR1431
DNAAF2Ciliary dyskinesiaAR114
DNAAF3Primary ciliary dyskinesiaAD/AR83
DNAAF5Ciliary dyskinesiaAR82
DNAH1Spermatogenic failure 18AR1025
DNAH5Ciliary dyskinesiaAR95160
DNAH11Ciliary dyskinesiaAR51101
DNAI1Ciliary dyskinesiaAR1429
DNAI2Ciliary dyskinesiaAR146
DNAJC21Bone marrow failure syndrome 3AR58
DNAL1Ciliary dyskinesiaAR31
DNMT3BImmunodeficiency-centromeric instability-facial anomalies syndromeAR1450
DOCK8Hyper-IgE recurrent infection syndrome, Mental retardation, autosomal dominant 2AR38162
DRC1Primary ciliary dyskinesiaAD/AR42
DYX1C1Ciliary dyskinesiaAR1111
EPG5Vici syndromeAR2950
ERCC6L2Bone marrow failure syndrome 2AR42
EXTL3Immunoskeletal dysplasia with neurodevelopmental abnormalities (ISDNA)AR47
FADDInfections, recurrent, with encephalopathy, hepatic dysfunction, and cardiovascular malformationsAR21
FASAutoimmune lymphoproliferative syndromeAD/AR28131
FASLGAutoimmune lymphoproliferative syndrome, type IBAD39
FERMT3Leukocyte adhesion deficiencyAR814
FOXN1T-cell immunodeficiency, congenital alopecia, and nail dystrophyAR46
FOXP3Immunodysregulation, polyendocrinopathy, and enteropathyXL2581
G6PC3Neutropenia, severe congenital, Dursun syndromeAR1237
G6PDGlucose-6-phosphate dehydrogenase deficiencyXL42222
GAS8Ciliary dyskinesia, primary, 33AR46
GATA2Myelodysplastic syndrome, Chronic neutropenia associated with monocytopenia, evolving to myelodysplasia and acute myeloid leukemia, Acute myeloid leukemia, Emberger syndrome, ImmunodeficiencyAD26105
GFI1Neutropenia, severe congenital, 2 autosomal dominant, Neutropenia, nonimmune chronic idiopathic, of adultsAD25
HAX1Neutropenia, severe congenitalAR919
HELLSImmunodeficiency-centromeric instability-facial anomalies syndrome 4AR66
HYDINPrimary ciliary dyskinesiaAD/AR515
HYOU1Combined immunodeficiencyAR2
ICOSImmunodeficiency, common variable, 1AR24
IFIH1Singleton-Merten syndrome, Aicardi-Goutieres syndrome 7AD1317
IFNAR2Immunodeficiency 45AR12
IKBKBImmunodeficiency 15AR26
IKZF1Immunodeficiency, common variable, 13AD712
IL1RNOsteomyelitis, sterile multifocal, with periostitis and pustulosisAR613
IL2RAInterleukin 2 receptor, alpha, deficiencyAR66
IL2RGCombined immunodeficiencyXL52220
IL7RSevere combined immunodeficiency, , T-cell negative, B-cell positive, NK cell positiveAR2047
IL10Graft vs. host diseaseAD13
IL10RAInflammatory bowel diseaseAR437
IL10RBInflammatory bowel diseaseAR217
IL12BImmunodeficiency 28, Immunodeficiency 29AR313
IL17RAImmunodeficiency 51AR615
IL17RCCandiasis, familial, 9AR43
IL21Immunodeficiency, common variable, 11AR11
IL21RImmunodeficiency, primary, autosomal recessive, IL21R-relatedAR39
IL36RNPustular psoriasis, generalizedAR623
IRAK4IRAK4 deficiency, Invasive pneumococcal disease, recurrent, isolated, 1AR1029
IRF2BP2Immunodeficiency, common variable, 14AD11
IRF8Immunodeficiency 32A (CD11C-positive/CD1C-positive dendritic cell deficiency), Immunodeficiency 32B (monocyte and dendritic cell deficiency)AD36
ISG15Immunodeficiency, with basal ganglia calcificationAR33
ITGB2Leukocyte adhesion deficiencyAR33114
ITKLymphoproliferative syndromeAR410
JAGN1Neutropenia, severe congenitalAR88
JAK1Primary immunodeficiencyAR44
JAK3Severe combined immunodeficiency, , T cell-negative, B cell-positive, natural killer cell-negativeAR2763
KRAS*Noonan syndrome, Cardiofaciocutaneous syndromeAD6134
LAMTOR2Immunodeficiency due to defect in MAPBP-interacting proteinAR11
LATImmunodeficiency 52AR218
LIG4Severe combined immunodeficiency with sensitivity to ionizing radiation, LIG4 syndromeAR1635
LPIN2Majeed syndromeAR912
LRBACommon variable immunodeficiencyAR1960
LRRC6Ciliary dyskinesiaAR717
LYSTChediak-Higashi syndromeAR4687
MAGT1Immunodeficiency, with magnesium defect, Epstein-Barr virus infection and neoplasia, Mental retardation, X-linked 95XL514
MAP3K14Primary immunodeficiency with multifaceted aberrant lymphoid immunityAR11
MASP13MC syndromeAR819
MEFVFamilial Mediterranean feverAD/AR27178
MKL1Primary immunodeficiencyAR3
MOGSCongenital disorder of glycosylationAR66
MRE11AAtaxia-telangiectasia-like disorder-1AR5751
MSN*Immunodeficiency 50XL22
MTHFD1Severe combined immunodeficiencyAR99
MVKMevalonic aciduria, Hyper-IgD syndrome, Porokeratosis 3, multiple typesAR30180
MYD88MYD88 deficiencyAR65
MYO5AGriscelli syndromeAR56
NBNBreast cancer, Nijmegen breakage syndromeAD/AR14187
NCF1Chronic granulomatous diseaseAR1838
NCF2Chronic granulomatous diseaseAR1364
NCF4Granulomatous diseaseAR42
NCSTNAcne inversa, familial 1AD629
NFKB1Common variable immunodeficiencyAD812
NFKB2Common variable immunodeficiencyAD611
NFKBIAEctodermal dysplasia, anhidrotic, with T-cell immunodeficiencyAD510
NHEJ1Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiationAR1415
NHP2Dyskeratosis congenitaAR33
NLRC4Autoinflammation with infantile enterocolitis (AIFEC), Familial cold autoinflammatory syndrome 4AD67
NLRP1Palmoplantar carcinoma, multiple self-healing, Autoinflammation with arthritis and dyskeratosisAD615
NLRP3Neonatal onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome, Chronic infantile neurologic cutaneous articular (CINCA) syndrome, Familial cold-induced autoinflammatory syndrome 1AD22129
NLRP12Familial cold autoinflammatory syndromeAD311
NME8Ciliary dyskinesiaAR15
NOD2Blau syndrome, Sarcoidosis, early-onsetAD/AR1263
NOP10Dyskeratosis congenitaAR11
NRASNoonan syndromeAD3114
NSMCE3Lung disease, immunodeficiency, and chromosome breakage syndrome (LICS)AR22
OFD1Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital syndrome, Joubert syndromeXL142157
ORAI1Immunodeficiency, Myopathy, tubular aggregate, 2AR913
OTULINAutoinflammation, panniculitis, and dermatosis syndrome (AIPDS)AR73
PARN*Pulmonary fibrosis and/or bone marrow failure, Dyskeratosis congenitaAD/AR1524
PEPDProlidase deficiencyAR1230
PGM3Immunodeficiency 23AR1314
PIGAMultiple congenital anomalies-hypotonia-seizures syndromeXL2424
PIH1D3Ciliary dyskinesia, primary, 36XL211
PIK3R1Agammaglobulinemia, SHORT syndromeAD/AR3223
PLCG2Familial cold autoinflammatory syndrome 3 (PLAID), Autoinflammation, antibody deficiency, and immune dysregulation syndrome (APLAID)AD79
PMS2Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposisAD/AR259324
PNPPurine nucleoside phosphorylase deficiencyAR1133
POLEColorectal cancer, Facial dysmorphism, immunodeficiency, livedo, and short stature syndrome (FILS syndrome)AD/AR750
POLE2Combined immunodeficiencyAR3
PRF1Lymphoma, non-Hodgkin, Aplastic anemia, adult-onset, Hemophagocytic lymphohistiocytosisAR22172
PRKCDAutoimmune lymphoproliferative syndrome type IIIAR35
PSENENAcne inversa, familial, 2AD715
PSMB8Nakajo-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 syndromeAR49
PSTPIP1Pyogenic sterile arthritis, pyoderma gangrenosum, and acneAD528
PTPRCSevere combined immunodeficiency, , T-cell negative, B-cell positive, NK cell positiveAR45
RAB27AGriscelli syndrome, Elejalde syndromeAR1753
RAC2Neutrophil immunodeficiency syndromeAD23
RAG1Omenn 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 granulomasAR48182
RAG2Omenn syndrome, Combined cellular and humoral immune defects with granulomasAR2679
RASGRP1Primary immunodeficiencyAR11
RBCK1Polyglucosan body myopathyAR1014
RECQL4Baller-Gerold syndrome, RAPADILINO syndrome, Rothmund-Thomson syndromeAR53100
RFX5Bare lymphocyte syndromeAR56
RFXANKMHC class II deficiencyAR614
RFXAPBare lymphocyte syndromeAR57
RHOHT-cell immunodeficiency with epidermodysplasia verruciformisAD/AR1
RLTPRCombined immunodeficiencyAR35
RMRPCartilage-hair hypoplasia, Metaphyseal dysplasia without hypotrichosis, Anauxetic dysplasiaAR34123
RNASEH2AAicardi-Goutières syndromeAR1321
RNASEH2BAicardi-Goutières syndromeAR1340
RNASEH2CAicardi-Goutières syndromeAR614
RNF31HOIP and LUBAC deficiencyAR1
RNF168RIDDLE syndromeAR44
RNU4ATACRoifman syndrome, Microcephalic osteodysplastic primordial dwarfism type 1, Microcephalic osteodysplastic primordial dwarfism type 3AR1521
RORCImmunodeficiency 42AR33
RPGRRetinitis pigmentosa, Cone-rod dystrophy, X-linked, 1, Macular degeneration, X-linked atrophic, Retinitis pigmentosa 3XL69203
RPSAAsplenia, isolated congenitalAD78
RSPH1Ciliary dyskinesiaAR1310
RSPH3Ciliary dyskinesia, primary, 32AR65
RSPH4ACiliary dyskinesiaAR1224
RSPH9Ciliary dyskinesiaAR611
RTEL1Pulmonary fibrosis and/or bone marrow failure, Dyskeratosis congenitaAD/AR3345
SAMD9Mirage syndrome, Tumoral calcinosis, normophosphatemicAR717
SAMD9LAtaxia-pancytopenia syndromeAD44
SAMHD1Aicardi-Goutières syndrome, Chilblain lupus 2AR2355
SBDSAplastic anemia, Shwachman-Diamond syndrome, Severe spondylometaphyseal dysplasiaAD/AR2190
SERPING1Angioedema, Complement component 4, partial deficiency ofAD/AR33536
SH2D1ALymphoproliferative syndromeXL15126
SLC7A7Lysinuric protein intoleranceAR5266
SLC29A3Histiocytosis-lymphadenopathy plus syndrome, DysosteosclerosisAR1624
SLC35C1Congenital disorder of glycosylation, Leukocyte adhesion deficiencyAR67
SLC37A4Glycogen storage diseaseAR29109
SLC46A1Folate malabsorptionAR1720
SMARCAL1Schimke immunoosseous dysplasiaAR1788
SMARCD2Specific granule defiency 2AR31
SP110Hepatic venoocclusive disease with immunodeficiencyAR77
SPAG1Primary ciliary dyskinesiaAD/AR1610
SPINK5Netherton syndromeAR2383
SRP72Bone marrow failure syndrome 1AD22
STAT3Hyper-IgE recurrent infection syndrome, Autoimmune disease, multisystem, infantile onsetAD44147
STAT5BGrowth hormone insensitivity with immunodeficiencyAR810
STIM1Stormorken syndrome, Immunodeficiency, Myopathy, tubular aggregate 1AD/AR1222
STK4T-cell immunodeficiency syndrome, recurrent infections, autoimmunity,AR37
STX11Hemophagocytic lymphohistiocytosis, familialAR618
STXBP2Hemophagocytic lymphohistiocytosis, familialAR969
TAP1Bare lymphocyte syndromeAR17
TAP2Bare lymphocyte syndromeAR28
TAPBPBare lymphocyte syndromeAR12
TBX1Conotruncal anomaly face syndromeAD1565
TCF3Agammaglobulinemia 8, autosomal dominantAD14
TCN2Transcobalamin II deficiencyAR933
TERCAplastic anemia, Pulmonary fibrosis and/or bone marrow failure, telomere-related, Dyskeratosis congenitaAD3867
TERTAplastic anemia, Pulmonary fibrosis and/or bone marrow failure, telomere-related, Dyskeratosis congenitaAD/AR43152
TFRCImmunodeficiency 46AR81
THBDThrombophilia due to thrombomodulin defect, Hemolytic uremic syndrome, atypicalAD522
TINF2Revesz syndrome, Dyskeratosis congenitaAD2337
TMC6Epidermodysplasia verruciformisAR57
TMC8Epidermodysplasia verruciformisAR39
TMEM173STING-associated vasculopathy, infantile-onsent (SAVI)AD310
TNFAIP3Autoinflammatory syndrome, familial, Behcet-likeAD812
TNFRSF1APeriodic fever (TNF receptor-associated periodic syndrome)AD20104
TNFRSF13BCommon variable immunodeficiency, Immunoglobulin A deficiencyAD/AR648
TRAF3IP2Candidiasis, familial 8AR13
TREX1Vasculopathy, retinal, with cerebral leukodystrophy, Chilblain lupus, Aicardi-Goutières syndromeAD/AR3068
TRNT1Retinitis pigmentosa and erythrocytic microcytosisAR1326
TTC7AGastrointestinal defects and immunodeficiency syndromeAR1944
UNC13DHemophagocytic lymphohistiocytosis, familialAR15156
UNC93B1Herpes simplex encephalitis, susceptibility to, 1AR2
UNC119Immunodeficiency, Cone-rod dystrophy 2AR15
UNGImmunodeficiency with hyper-IgM, type 5AD47
USB1Poikiloderma with neutropeniaAR2322
USP18Pseudo-TORCH syndrome 2AR341
VPS13BCohen syndromeAR248199
VPS45Neutropenia, severe congenital, 5, autosomal recessiveAR34
WASNeutropenia, severe congenital, Thrombocytopenia, Wiskott-Aldrich syndromeXL53435
WIPF1Wiskott-Aldrich syndrome 2AR22
WRAP53Dyskeratosis congenitaAR75
XIAPLymphoproliferative syndromeXL983
ZAP70Selective T-cell defectAR1426
ZBTB24Immunodeficiency-Centromeric Instability-Facial Anomalies 2AR717
ZMYND10Ciliary dyskinesiaAR716

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number

Panel Update

Genes added

Genes removed

Test strength and Limitations

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: *PPA2* (11, 12). 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. 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 GHC Genetics.

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

Test Performance

The GHC Genetics panel covers classical genes associated with Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), cardiac arrest underlying cardiac condition, cardiac arrest cause unspecified, syncope and collapse, abnormal ECG, Long QT syndrome, arrhythmogenic right ventricular cardiomyopathy (ARVC) and Short QT syndrome. 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 GHC 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%

Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Detection of Del/Dup of several genes is by MLPA analysis (MS Holland). All genes are performed by CNV analysis through the genome depending on exon size, sequencing coverage and sequence content. We have validated the assays for different starting materials including isolated DNA from EDTA blood that provide high-quality results.

Bioinformatics & clinical interpretation

The sequencing data generated in our laboratory is analysed by our bioinformatic pipeline, integrating state-of-the art algorithms and industry-standard software solutions. We use also JSI medical systems software for sequencing data analysis. JSI medical systems is a certified system offering sophisticated bioinformatic software solutions covering a wide field of sequencing techniques.

Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results.

Every pathogenic or probably pathogenic variant is confirmed by the Sanger sequencing method. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. The analysis of detected variants was performed on the basis of the reference database of polymorphisms and international mutation databases: UMD, LOVD and ClinVar.

The consequence of variants in coding and splice regions are estimated using Alamut software. The Alamut database contains more than 28000 coding genes, non-protein coding genes and pseudogenes. This database (shared with the high throughput annotation engine for NGS data, Alamut Batch) is frequently updated. Information comes from different public databases such as NCBI, EBI, and UCSC, as well as other sources including gnomAD, ESP, Cosmic, ClinVar, or HGMD and CentoMD (for those a separate subscription from Qiagen/Biobase and Centogene respectively is required). Alamut Visual finds information about nucleotide conservation data through many vertebrates’ species, with the phastCons and phyloP scores, amino acid conservation data through orthologue alignments and information on protein domains.

Moreover, we integrate several missense variant pathogenicity prediction tools and algorithms such as SIFT, PolyPhen, AlignGVGD or MutationTaster. It also offers a window dedicated to the in silico study of variants’ effect on RNA splicing, allowing the assessment of their potential impact on splice junctions and visualization of cryptic or de novo splice sites. Impact on splicing regulation is also assessed.

Clinical interpretation

At GHC Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical report. We recommend an interpretation of the findings of this molecular genetic analysis, including subsequent oncological consultation for the patient in the context of genetic counselling for the patient.

We strive to continuously monitor current genetic literature identifying new relevant information and findings and adapting them to our diagnostics. This enables relevant novel discoveries to be rapidly translated and adopted into our ongoing diagnostics development without delay. The undertaking of such comprehensive due diligence ensures that our diagnostic panels and clinical statements are the most up-to-date on the market.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. 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 analysed at our laboratories enables 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 three times at GHC Genetics. Reported variants of uncertain significance (VUS) 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 GHC 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, 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 counselling.

Our Clinical interpretation team analyses 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 laboratories are therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by GHC Genetics is re-classified, our laboratories will issue a follow-up statement to the original ordering health care provider at no additional cost.