Clinical Tests
Panels
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
PLUS SEQ DEL/DUP	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.

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

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

Genes added

Genes removed

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.

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.

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.