Clinical Tests
Panels
Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders

Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel

332 gene panel that includes assessment of non-coding variants

This panel covers the majority of the genes listed in the Nosology 2015 (PMID: 26394607) and all genes in our Malformation category that cause growth retardation, short stature or skeletal dysplasia and is therefore a powerful diagnostic tool. It is ideal for patients suspected to have a syndromic or an isolated growth disorder or a skeletal dysplasia.

Analysis methods	Availability	Number of genes	Test code	CPT codes
PLUS SEQ DEL/DUP	4 weeks	332	GHC0119	SEQ 81405 SEQ 81406 SEQ 81408 DEL/DUP 81479

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.

This panel covers a broad spectrum of diseases associated with growth retardation, short stature or skeletal dysplasia. Many of these conditions have overlapping features which can make clinical diagnosis a challenge. Genetic diagnostics is therefore the most efficient way to subtype the diseases and enable individualized treatment and management decisions. Moreover, detection of causative mutations establishes the mode of inheritance in the family which is essential for informed genetic counseling. For additional information regarding the conditions tested on this panel, please refer to the National Organization for Rare Disorders and / or GeneReviews.

Genes in the Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel and their clinical significance

Gene	Associated phenotypes	Inheritance	ClinVar	HGMD
ACAN#	Spondyloepimetaphyseal dysplasia, aggrecan type, Spondyloepiphyseal dysplasia, Kimberley type, Osteochondritis dissecans, short stature, and early-onset osteoarthritis	AD/AR	18	30
ACP5	Spondyloenchondrodysplasia with immune dysregulation	AR	11	26
ACTB	Baraitser-Winter syndrome	AD	46	54
ACTG1	Deafness, Baraitser-Winter syndrome	AD	25	43
ACVR1	Fibrodysplasia ossificans progressiva	AD	14	19
ADAMTS10	Weill-Marchesani syndrome	AR	8	13
ADAMTS17	Weill-Marchesani-like syndrome	AR	6	7
ADAMTSL2	Geleophysic dysplasia	AR	8	28
AGPS	Rhizomelic chondrodysplasia punctata type 3	AR	4	8
AIFM1	Deafness, Combined oxidative phosphorylation deficiency 6, Cowchock syndrome	XL	27	29
AKT1	Proteus syndrome, Cowden syndrome	AD	5	6
ALPL	Odontohypophosphatasia, Hypophosphatasia perinatal lethal, infantile, juvenile and adult forms	AD/AR	61	290
ALX3	Frontonasal dysplasia type 1	AR	7	7
ALX4	Frontonasal dysplasia type 2, Parietal foramina	AD/AR	15	23
AMER1	Osteopathia striata with cranial sclerosis	XL	14	38
ANKH	Calcium pyrophosphate deposition disease (familial chondrocalcinosis type 2), Craniometaphyseal dysplasia autosomal dominant type	AD	12	20
ANKRD11	KBG syndrome	AD	119	122
ANO5	Gnathodiaphyseal dysplasia, LGMD2L and distal MMD3 muscular dystrophies	AD/AR	60	115
ARHGAP31	Adams-Oliver syndrome	AD	2	4
ARSB	Mucopolysaccharidosis (Maroteaux-Lamy)	AR	27	199
ARSE	Chondrodysplasia punctata X-linked recessive, brachytelephalangic type (CDPX1)	XL	21	46
ATP6V0A2	Cutis laxa, Wrinkly skin syndrome	AR	16	54
ATR	Cutaneous telangiectasia and cancer syndrome, Seckel syndrome	AD/AR	8	18
B3GALT6	Spondyloepimetaphyseal dysplasia with joint laxity, Ehlers-Danlos syndrome	AR	17	26
B3GAT3	Multiple joint dislocations, short stature, craniofacial dysmorphism, and congenital heart defects	AR	5	13
B4GALT7	Ehlers-Danlos syndrome, progeroid form	AR	9	9
BCS1L	Bjornstad syndrome, GRACILE syndrome, Leigh syndrome, Mitochondrial complex III deficiency, nuclear type 1	AR	33	37
BGN	Spondyloepimetaphyseal dysplasia, X-linked, Meester-Loeys syndrome	XL	8	7
BHLHA9	Syndactyly Malik-Percin type, mesoaxial synostotic, with phalangeal reduction, Split hand-foot malformation with long bone deficiency (SHFLD3), Gollop-Wolfgang	AR	4	37
BMP1	Osteogenesis imperfecta	AR	7	15
BMP2	Brachydactyly type A2	AD	5	28
BMPER	Diaphanospondylodysostosis	AR	5	17
BMPR1B	Acromesomelic dysplasia, Demirhan, Brachydactyly C/Symphalangism-like pheno, Brachydactyly type A2	AD/AR	12	16
BRAF	LEOPARD syndrome, Noonan syndrome, Cardiofaciocutaneous syndrome	AD	135	65
BRCA2	Fanconi anemia, Medulloblastoma, Glioma susceptibility, Pancreatic cancer, Wilms tumor, Breast-ovarian cancer, familial	AD/AR	2959	2364
BRIP1	Fanconi anemia, Breast cancer	AD/AR	182	166
CA2	Osteopetrosis, with renal tubular acidosis	AR	9	31
CANT1	Desbuquois dysplasia	AR	20	28
CASR	Hypocalcemia, Neonatal hyperparathyroidism, Familial Hypocalciuric hypercalcemia with transient Neonatal hyperparathyroidism	AD/AR	103	393
CBL	Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia	AD	23	38
CCDC8	Three M syndrome 3	AR	2	3
CDC6	Meier-Gorlin syndrome (Ear-patella-short stature syndrome)	AR	2	2
CDC45	Meier-Gorlin syndrome 7	AR	10	19
CDKN1C	Beckwith-Wiedemann syndrome, IMAGE syndrome	AD	28	81
CDT1	Meier-Gorlin syndrome (Ear-patella-short stature syndrome)	AR	6	11
CENPJ	Seckel syndrome, Microcephaly	AR	32	9
CEP63	Seckel syndrome	AR	7	2
CEP152	Seckel syndrome, Microcephaly	AR	19	20
CHST3	Spondyloepiphyseal dysplasia with congenital joint dislocations (recessive Larsen syndrome)	AR	19	36
CHST14	Ehlers-Danlos syndrome, musculocontractural	AR	14	21
CHSY1	Temtamy preaxial brachydactyly syndrome	AR	6	11
CKAP2L	Filippi syndrome	AR	7	7
CLCN5	Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis, Hypophosphatemic rickets,, Nephrolithiasis, I, Dent disease	XL	45	267
CLCN7	Osteopetrosis	AD/AR	13	95
COL1A1	Ehlers-Danlos syndrome, Caffey disease, Osteogenesis imperfecta type 1, Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4	AD	290	943
COL1A2	Ehlers-Danlos syndrome, cardiac valvular form, Osteogenesis imperfecta type 1, Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4	AD/AR	162	496
COL2A1	Avascular necrosis of femoral head, Rhegmatogenous retinal detachment, Epiphyseal dysplasia, with myopia and deafness, Czech dysplasia, Achondrogenesis type 2, Platyspondylic dysplasia Torrance type, Hypochondrogenesis, Spondyloepiphyseal dysplasia congenital (SEDC), Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type, Kniest dysplasia, Spondyloperipheral dysplasia, Mild SED with premature onset arthrosis, SED with metatarsal shortening, Stickler syndrome type 1	AD	166	544
COL3A1	Ehlers-Danlos syndrome	AD	499	625
COL5A1	Ehlers-Danlos syndrome	AD	84	151
COL5A2	Ehlers-Danlos syndrome	AD	21	34
COL9A1	Stickler syndrome recessive type, Multiple epiphyseal dysplasia type 6 (EDM6)	AR	9	5
COL9A2	Stickler syndrome, Multiple epiphyseal dysplasia type 2 (EDM2)	AD/AR	7	12
COL9A3	Multiple epihyseal dysplasia type 3 (EDM3)	AD/AR	10	15
COL10A1	Metaphyseal chondrodysplasia, Schmid	AD	21	51
COL11A1	Marshall syndrome, Fibrochondrogenesis, Stickler syndrome type 2	AD/AR	30	86
COL11A2	Weissenbacher-Zweymuller syndrome, Deafness, Otospondylomegaepiphyseal dysplasia, Fibrochondrogenesis, Stickler syndrome type 3 (non-ocular)	AD/AR	28	55
COMP	Pseudoachondroplasia, Multiple ephiphyseal dysplasia	AD	43	184
CREB3L1	Osteogenesis imperfecta, type XVI	AR		1
CREBBP	Rubinstein-Taybi syndrome	AD	156	348
CRTAP	Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4	AR	12	28
CSPP1	Jeune asphyxiating thoracic dystrophy, Joubert syndrome	AR	27	27
CTSK	Pycnodysostosis	AR	25	54
CUL7	3-M syndrome, Yakut short stature syndrome	AR	26	80
CYP27B1	Vitamin D-dependent rickets	AR	23	73
DDR2	Spondylometaepiphyseal dysplasia, short limb-hand type	AR	11	7
DHCR7	Smith-Lemli-Opitz syndrome	AR	67	216
DHCR24	Desmosterolosis	AR	6	8
DHODH	Postaxial acrofacial dysostosis (Miller syndrome)	AR	8	20
DLL3	Spondylocostal dysostosis	AR	11	23
DLL4	Adams-Oliver syndrome	AD	10	12
DLX3	Amelogenesis imperfecta, Trichodontoosseous syndrome	AD	5	6
DLX5	Split-hand/foot malformation with sensorineural hearing loss	AR	3	8
DMP1	Hypophosphatemic rickets	AR	5	10
DOCK6	Adams-Oliver syndrome	AR	21	19
DVL1	Robinow syndrome	AD	16	17
DYM	Dyggve-Melchior-Clausen dysplasia, Smith-McCort dysplasia	AR	21	34
DYNC2H1	Short -rib thoracic dysplasia with or without polydactyly type 1, Short -rib thoracic dysplasia with or without polydactyly type 3, Asphyxiating thoracic dysplasia (ATD; Jeune), SRPS type 2 (Majewski)	AR/Digenic	144	109
EBP	Chondrodysplasia punctata, Male EBP disorder with neurologic defects (MEND)	XL	43	90
EFNB1	Craniofrontonasal dysplasia	XL	27	115
EFTUD2	Mandibulofacial dysostosis with microcephaly, Esophageal atresia, syndromic	AD	43	93
EIF2AK3	SED, Wolcott-Rallison type	AR	9	78
ENAM	Amelogenesis imperfecta	AR	8	18
ENPP1	Arterial calcification, Hypophosphatemic rickets	AR	20	68
EOGT	Adams-Oliver syndrome	AR	3	5
EP300	Rubinstein-Taybi syndrome	AD	57	91
ERCC4	Fanconi anemia, Xeroderma pigmentosum, XFE progeroid syndrome	AR	11	59
ESCO2	SC phocomelia syndrome, Roberts syndrome	AR	29	30
EVC	Weyers acrofacial dysostosis, Ellis-van Creveld syndrome	AD/AR	22	80
EVC2	Ellis-van Creveld syndrome, Weyers acrodental dysostosis	AD/AR	34	67
EXT1	Multiple cartilagenious exostoses 1	AD	67	497
EXT2	Multiple cartilagenious exostoses 2	AD	32	242
EXTL3	Immunoskeletal dysplasia with neurodevelopmental abnormalities (ISDNA)	AR	4	7
EZH2	Weaver syndrome	AD	29	40
FAM20A	Amelogenesis imperfecta (Enamel-renal syndrome)	AR	17	41
FAM20C	Hypophosphatemia, hyperphosphaturia, dental anomalies, intracerebral calcifications and osteosclerosis (Raine syndrome)	AR	13	23
FAM58A	Toe syndactyly, telecanthus, and anogenital and renal malformations (STAR syndrome)	XL	8	11
FAM83H	Amelogenesis imperfecta	AD	14	29
FAM111A	Kenny-Caffey syndrome, type 2	AD	4	9
FANCA	Fanconi anemia	AR	76	541
FANCB	Fanconi anemia	XL	10	20
FANCC	Fanconi anemia	AR	70	58
FANCD2*	Fanconi anemia	AR	14	57
FANCE	Fanconi anemia	AR	5	16
FANCF	Fanconia anemia	AR	7	16
FANCG	Fanconi anemia	AR	13	89
FANCI	Fanconi anemia	AR	12	43
FANCL	Fanconi anemia	AR	7	22
FANCM	Fanconi anemia	AR	2	49
FBN1	MASS syndrome, Marfan syndrome, Acromicric dysplasia, Geleophysic dysplasia	AD	919	2548
FBN2	Congenital contractural arachnodactyly (Beals syndrome)	AD	45	95
FGD1	Aarskog-Scott syndrome, Mental retardation, syndromic	XL	26	49
FGF10	Aplasia of lacrimal and salivary glands	AD	9	12
FGF23	Tumoral calcinosis, hyperphosphatemic, Hypophosphatemic rickets	AD/AR	10	16
FGFR1	Pfeiffer syndrome, Trigonocephaly, Hypogonadotropic hypogonadism, Osteoglophonic Dwarfism - Craniostenosis, Hartsfield syndrome	AD/Digenic/Multigenic	69	241
FGFR2	Apert syndrome, Pfeiffer syndrome, Jackson-Weiss syndrome, Lacrimoauriculodentodigital syndrome, Beare-Stevenson cutis gyrata syndrome, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis, Craniofacial-skeletal-dermatological dysplasia, Crouzon syndrome, Bent bone dysplasia	AD	93	150
FGFR3	Lacrimoauriculodentodigital syndrome, Muenke syndrome, Crouzon syndrome with acanthosis nigricans, Camptodactyly, tall stature, and hearing loss (CATSHL) syndrome, Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia type 1, Thanatophoric dysplasia type 2, SADDAN	AD/AR	53	72
FKBP10	Bruck syndrome type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4	AR	20	37
FLNA	Frontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defects	XL	119	235
FLNB	Larsen syndrome (dominant), Atelosteogenesis type 1, Atelosteogenesis type 3, Spondylo-carpal-tarsal dyspasia	AD/AR	41	103
GALNT3	Tumoral calcinosis, hyperphosphatemic	AR	16	34
GDF5	Multiple synostoses syndrome, Fibular hypoplasia and complex brachydactyly, Acromesomelic dysplasia, Hunter-Thompson, Symphalangism, proximal, Chondrodysplasia, Brachydactyly type A2, Brachydactyly type C, Grebe dysplasia	AD/AR	23	50
GH1	Isolated growth hormone deficiency, Kowarski syndrome	AD/AR	25	86
GHR	Growth hormone insensitivity syndrome (Laron syndrome)	AD/AR	35	109
GHRHR	Isolated growth hormone deficiency	AR	13	43
GJA1	Oculodentodigital dysplasia mild type, Oculodentodigital dysplasia severe type, Syndactyly type 3	AD/AR	32	106
GLI2	Culler-Jones syndrome	AD	26	76
GLI3	Acrocallosal syndrome, Pallister-Hall syndrome, Grieg cephalopolysndactyly syndrome, Postaxial polydactyly type A, Preaxial polydactyly type 3, Preaxial polydactyly type 4	AD	63	229
GNAS	McCune-Albright syndrome, Progressive osseous heteroplasia, Pseudohypoparathyroidism, Albright hereditary osteodystrophy	AD	62	265
GNPAT	Rhizomelic chondrodysplasia punctata, rhizomelic	AR	8	14
GPC6	Omodysplasia 1	AR	11	9
HDAC8	Cornelia de Lange syndrome	XL	33	44
HESX1	Septooptic dysplasia, Pituitary hormone deficiency, combined	AR/AD	14	26
HOXA13	Hand-foot-uterus syndrome, Hand-foot-genital syndrome, Guttmacher syndrome	AD	8	24
HOXD13	Brachydactyly-syndactyly syndrome, Synopolydactyly, Syndactyly, Synopolydactyly with clefting, Brachydactyly type D	AD/AR	18	40
HRAS	Costello syndrome, Congenital myopathy with excess of muscle spindles	AD	41	29
HSPG2	Schwartz-Jampel syndrome, Dyssegmental dysplasia Silverman-Handmaker type, Dyssegmental dysplasia Rolland-Desbuquis type	AD/AR	16	56
IDS	Mucopolysaccharidosis	XL	80	631
IFITM5	Osteogenesis imperfecta type 5	AD	2	2
IFT43	Cranioectodermal dysplasia 3	AR	4	6
IFT80	Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune)	AR	11	7
IFT122	Sensenbrenner syndrome, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2	AR	11	21
IFT140	Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune)	AR	37	54
IFT172	Retinitis pigmentosa, Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune)	AR	21	23
IGF1	Insulin-like growth factor I deficiency	AR	4	8
IGF1R	Insulin-like growth factor I, resistance	AD/AR	12	61
IGFALS	Insulin-like growth factor-binding protein, acid-labile subunit, deficiency	AR	5	33
IHH	Acrocapitofemoral dysplasia, Brachydactyly, Syndactyly type Lueken	AD/AR	12	20
IMPAD1	Chondrodysplasia with joint dislocations, GPAPP type	AR	5	5
INPPL1	Opsismodysplasia	AR	17	32
INSR	Hyperinsulinemic hypoglycemia, familial, Rabson-Mendenhall syndrome, Donohoe syndrome	AD/AR	44	183
IRS1	Diabetes mellitus, noninsulin-dependent	AD/AR	3	16
KAT6B	Ohdo syndrome, SBBYS variant, Genitopatellar syndrome	AD	38	62
KIF7	Acrocallosal syndrome, Hydrolethalus syndrome, Al-Gazali-Bakalinova syndrome, Joubert syndrome	AR/Digenic	23	40
KIF22	Spondyloepimetaphyseal dysplasia with joint laxity, type 2	AD	4	4
KMT2A	Wiedemann-Steiner syndrome	AD	107	83
KRAS	Noonan syndrome, Cardiofaciocutaneous syndrome	AD	61	34
LARP7	Alazami syndrome	AR	16	6
LBR	Pelger-Huet anomaly, Reynolds syndrome, Greenberg/HEM skeletal dysplasia, Hydrops-ectopic calcification-moth-eaten skeletal dysplasia	AD	18	23
LEMD3	Buschke-Ollendorff syndrome, Osteopoikilosis	AD	11	31
LHX3	Pituitary hormone deficiency, combined	AR	9	16
LHX4	Pituitary hormone deficiency, combined	AD	10	23
LIFR	Stuve-Wiedemann dysplasia, Schwartz-Jampel type 2 syndrome	AR	11	32
LMNA	Heart-hand syndrome, Slovenian, Limb-girdle muscular dystrophy, Muscular dystrophy, congenital, LMNA-related, Lipodystrophy (Dunnigan), Emery-Dreiffus muscular dystrophy, Malouf syndrome, Dilated cardiomyopathy (DCM), Mandibuloacral dysplasia type A, Progeria Hutchinson-Gilford type	AD/AR	231	553
LMX1B	Nail-patella syndrome	AD	26	192
LONP1	Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies (CODAS) syndrome	AR	7	16
LRP4	Cenani-Lenz syndactyly syndrome, Sclerosteosis, Myasthenic syndrome, congenital	AD/AR	13	24
LRP5	Van Buchem disease, Osteoporosis-pseudoglioma syndrome, Hyperostosis, endosteal, Osteosclerosis, Exudative vitreoretinopathy, Osteopetrosis late-onset form type 1, LRP5 primary osteoporosis	AD/AR/Digenic	55	188
LTBP2	Weill-Marchesani syndrome, Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, Glaucoma, primary congenital	AR	21	26
LTBP3	Dental anomalies and short stature	AR	15	10
LZTR1	Schwannomatosis, Noonan syndrome	AD	27	64
MAFB	Multicentric carpotarsal osteolysis	AD	13	22
MAP2K1	Cardiofaciocutaneous syndrome	AD	45	21
MAP2K2	Cardiofaciocutaneous syndrome	AD	21	35
MATN3	Spondyloepimetaphyseal dysplasia Matrilin type, Multiple epiphyseal dysplasia type 5 (EDM5)	AD/AR	8	24
MBTPS2	Keratosis follicularis spinulosa decalvans, IFAP syndrome, Palmoplantar keratoderma, mutilating, with periorificial keratotic plaques	XL	10	24
MESP2	Spondylocostal dysostosis 2, autosomal recessive	AR	7	5
MGP	Keutel syndrome	AR	5	7
MMP2	Torg-Winchester syndrome, Multicentric osteolysis, nodulosis, and arthropathy	AR	8	22
MMP9	Metaphyseal anadysplasia	AR	1	6
MMP13	Metaphyseal anadysplasia 1, Metaphyseal dysplasia, Spahr type, Spondyloepimetaphyseal dysplasia, Missouri type	AD/AR	7	6
MSX2	Parietal foramina, Parietal foramina with cleidocranial dysplasia, Craniosynostosis Boston type	AD	9	25
MYCN	Feingold syndrome	AD	25	40
NANS	Spondyloepimetaphyseal dysplasiam Genevieve type	AR	8	12
NEK1	Short -rib thoracic dysplasia with or without polydactyly, SRPS type 2 (Majewski)	AR/Digenic	21	20
NF1	Watson syndrome, Neurofibromatosis, Neurofibromatosis-Noonan syndrome	AD	810	2703
NFIX	Marshall-Smithsyndrome	AD	43	65
NIPBL	Cornelia de Lange syndrome	AD	290	419
NKX3-2	Spondylo-megaepiphyseal-metaphyseal dysplasia	AR	3	4
NOG	Tarsal-carpal coalition syndrome, Multiple synostosis syndrome, Stapes ankylosis with broad thumb and toes (Teunissen-Cremers syndrome), Symphalangism, proximal, Brachydactyly type B2	AD	20	62
NOTCH1	Aortic valve disease	AD	44	91
NOTCH2	Alagille syndrome, Hajdu-Cheney syndrome	AD	35	63
NPR2	Acromesomelic dysplasia type Maroteaux, Epiphyseal chondrodysplasia, Miura, Short stature with nonspecific skeletal abnormalities	AD/AR	30	67
NRAS	Noonan syndrome	AD	31	14
NSD1	Sotos syndrome, Weaver syndrome, Beckwith-Wiedemann syndrome	AD	303	515
NSDHL	Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome), CK syndrome	XL	15	28
OBSL1	3-M syndrome	AR	13	33
ORC1	Meier-Gorlin syndrome (Ear-patella-short stature syndrome)	AR	9	9
ORC4	Meier-Gorlin syndrome (Ear-patella-short stature syndrome)	AR	22	6
ORC6	Meier-Gorlin syndrome (Ear-patella-short stature syndrome)	AR	7	6
OSTM1	Osteopetrosis, autosomal recessive 5	AR	5	9
OTX2	Microphthalmia, syndromic, Pituitary hormone deficiency, combined, Retinal dystrophy, early-onset, and pituitary dysfunction	AD	21	68
P3H1	Osteogenesis imperfecta	AR	15	55
PALB2	Fanconi anemia, Pancreatic cancer, Breast cancer	AD/AR	422	358
PAPSS2	Brachyolmia 4 with mild epiphyseal and metaphyseal changes, SEMD PAPPS2 type	AR	11	19
PCNT	Microcephalic osteodysplastic primordial dwarfism	AR	48	84
PCYT1A	Spondylometaphyseal dysplasia with cone-rod dystrophy	AR	12	20
PDE4D	Acrodysostosis 2, with or without hormone resistance	AD	14	36
PEX7	Refsum disease, Rhizomelic CDP type 1	AR	37	52
PEX14	Peroxisome biogenesis factor disorder 14, Zellweger syndrome	AR	5	4
PEX19	Peroxisome biogenesis disorder, 19, Zellweger syndrome	AR	3	3
PGM3	Immunodeficiency 23	AR	13	14
PHEX	Hypophosphatemic rickets	XL	262	428
PIK3CA	Cowden syndrome, CLOVES	AD	86	53
PITX2	Axenfeld-Rieger syndrome, Ring dermoid of cornea, Iridogoniodysgenesis, Peters anomaly	AD	23	96
PLOD2	Bruck syndrome, Osteogenesis imperfecta type 3	AR	8	17
PLS3	Osteoporosis and osteoporotic fractures	XL	1	14
POC1A	Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis (SOFT syndrome)	AR	4	8
POLR1C	Treacher Collins syndrome	AR	16	20
POLR1D	Treacher Collins syndrome	AD/AR	8	26
POR	Disordered steroidogenesis due to cytochrome p450 oxidoreductase deficiency, Antley-Bixler syndrome	AR	12	68
POU1F1	Pituitary hormone deficiency, combined	AR	19	41
PPIB	Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4	AR	8	13
PRKAR1A	Myxoma, intracardiac, Acrodysostosis, Pigmented nodular adrenocortical disease, Carney complex	AD	66	180
PROP1	Pituitary hormone deficiency, combined	AR	27	37
PTDSS1	Lenz-Majewski hyperostotic dwarfism	AD	5	5
PTH1R	Metaphyseal chondrodysplasia Jansen type, Failure of tooth eruption, Eiken dysplasia, Blomstrand dysplasia	AD/AR	13	40
PTHLH	Brachydactyly, type E2	AD	5	17
PTPN11	Noonan syndrome, Metachondromatosis	AD	128	139
PYCR1	Cutis laxa AR type 2B	AR	19	38
RAB33B	Dyggve-Melchior-Clausen syndrome, Smith-McCort dysplasia 2	AR	6	7
RAD21	Cornelia de Lange syndrome 4	AD	9	11
RAD51C	Fanconi anemia, Breast-ovarian cancer, familial	AD/AR	92	112
RAF1	LEOPARD syndrome, Noonan syndrome, Dilated cardiomyopathy (DCM)	AD	44	48
RASA2	Noonan syndrome	AD	1	3
RBBP8	Seckel syndrome, Jawad syndrome	AR	6	6
RBM8A	Thrombocytopenia - absent radius	AD/AR	4	10
RBPJ	Adams-Oliver syndrome	AD	4	5
RECQL4	Baller-Gerold syndrome, RAPADILINO syndrome, Rothmund-Thomson syndrome	AR	53	100
RIT1	Noonan syndrome	AD	20	25
RMRP	Cartilage-hair hypoplasia, Metaphyseal dysplasia without hypotrichosis, Anauxetic dysplasia	AR	34	123
RNU4ATAC	Roifman syndrome, Microcephalic osteodysplastic primordial dwarfism type 1, Microcephalic osteodysplastic primordial dwarfism type 3	AR	15	21
ROR2	Robinow syndrome recessive type, Brachydactyly type B	AD/AR	19	40
RRAS	Noonan-syndrome like phenotype	AD/AR		2
RTTN	Microcephaly, short stature, and polymicrogyria with or without seizures	AR	13	10
RUNX2	Cleidocranial dysplasia, Metaphyseal dysplasia with maxillary hypoplasia	AD	21	213
SALL1	Townes-Brocks syndrome 1	AD	27	84
SALL4	Acro-renal-ocular syndrome, Duane-radial ray/Okohiro syndrome	AD	19	55
SBDS*	Aplastic anemia, Shwachman-Diamond syndrome, Severe spondylometaphyseal dysplasia	AD/AR	21	90
SEC24D	Cole-Carpenter syndrome 2	AR	4	11
SERPINF1	Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4	AR	9	35
SERPINH1	Osteogenesis imperfecta type 3	AR	3	3
SETBP1	Mental retardation, autosomal dominant 29, Schinzel-Giedion midface retraction syndrome	AD	21	40
SF3B4	Acrofacial dysostosis 1, Nager	AD	27	36
SH3BP2	Cherubism	AD	9	16
SH3PXD2B	Frank-ter Haar syndrome	AR	9	18
SHOC2	Noonan-like syndrome with loose anagen hair	AD	2	4
SHOX	Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia, Short stature	XL/PAR	25	426
SKI	Shprintzen-Goldberg syndrome	AD	17	21
SLC26A2	Diastrophic dysplasia, Atelosteogenesis type 2, De la Chapelle dysplasia, Recessive Multiple Epiphyseal dysplasia, Achondrogenesis type 1B	AR	55	50
SLC29A3	Histiocytosis-lymphadenopathy plus syndrome, Dysosteosclerosis	AR	16	24
SLC34A3	Hypophosphatemic rickets with hypercalciuria	AR	22	36
SLC35D1	Schneckenbecken dysplasia	AR	7	7
SLC39A13	Spondylodysplastic Ehlers-Danlos syndrome	AR	2	8
SLCO2A1	Hypertrophic osteoarthropathy	AD/AR	13	71
SLX4	Fanconi anemia	AR	14	54
SMAD3	Aneurysms-osteoarthritis syndrome, Loeys-Dietz syndrome	AD	43	55
SMAD4	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Polyposis, juvenile intestinal, Myhre dysplasia, Hereditary hemorrhagic telangiectasia	AD	162	141
SMARCAL1	Schimke immunoosseous dysplasia	AR	17	88
SMC1A	Cornelia de Lange syndrome	XL	56	87
SMC3	Cornelia de Lange syndrome	AD	21	20
SNX10	Osteopetrosis, autosomal recessive 8	AR	3	13
SOS1	Noonan syndrome	AD	45	67
SOST	Craniodiaphyseal dysplasia, autosomal dominant, Sclerosteosis 1, van Buchem disease	AD/AR	6	14
SOX2	Microphthalmia, syndromic	AD	31	100
SOX3	Panhypopituitarism	XL	4	25
SOX9	Campomelic dysplasia, 46,XY sex reversal, Brachydactyly with anonychia (Cooks syndrome)	AD	44	141
SP7	Osteogenesis imperfecta, type XII	AR	1	1
SPARC	Keratoconus, Osteogenesis imperfecta, type XVII	AD/AR	2	3
SRCAP	Floating-Harbor syndrome	AD	13	40
STAMBP	Microcephaly-capillary malformation syndrome	AR	14	19
STAT5B	Growth hormone insensitivity with immunodeficiency	AR	8	10
TBX3	Ulnar-Mammary syndrome	AD	6	20
TBX4	Small patella syndrome	AD	5	30
TBX5	Holt-Oram syndrome	AD	55	126
TBX6	Spondylocostal dysostosis 5	AD	9	34
TBX15	Cousin syndrome	AR	2	3
TBX19	Adrenocorticotropic hormone deficiency	AR	8	27
TCF12	Craniosynostosis	AD	21	53
TCIRG1	Osteopetrosis, severe neonatal or infantile forms (OPTB1)	AD/AR	14	130
TCOF1	Treacher Collins syndrome	AD	42	320
TCTN3	Orofaciodigital syndrome (Mohr-Majewski syndrome), Joubert syndrome	AR	9	10
TGFB1	Diaphyseal dysplasia Camurati-Engelmann	AD	15	18
TGFB2	Loeys-Dietz syndrome	AD	34	28
TGFB3	Loeys-Dietz syndrome (Reinhoff syndrome), Arrhythmogenic right ventricular dysplasia	AD	17	22
TGFBR1	Loeys-Dietz syndrome	AD	37	69
TGFBR2	Loeys-Dietz syndrome	AD	58	136
TMEM38B	Osteogenesis imperfecta, type XIV	AR	2	6
TNFRSF11A	Familial expansile osteolysis, Paget disease of bone, Osteopetrosis, severe neonatal or infantile forms (OPTB1)	AD/AR	8	23
TNFRSF11B	Paget disease of bone, juvenile	AR	8	18
TNFSF11	Osteopetrosis, autosomal recessive 2	AR	3	5
TP63	Rapp-Hodgkin syndrome, Orofacial cleft, ADULT syndrome, Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome, Ankyloblepharon-ectodermal defects-cleft lip/palate, Split-hand/foot malformation, Limb-mammary syndrome	AD	55	116
TRAPPC2	Spondyloepiphyseal dysplasia tarda	XL	12	54
TRIM37	Mulibrey nanism	AR	19	21
TRIP11	Achondrogenesis, type IA	AR	7	13
TRPS1	Trichorhinophalangeal syndrome type 1, Trichorhinophalangeal syndrome type 3	AD	59	139
TRPV4	Metatropic dysplasia, Spondyloepiphyseal dysplasia Maroteaux type, Parastremmatic dwarfism, Hereditary motor and sensory neuropathy, Spondylometaphyseal dysplasia Kozlowski type, Spinal muscular atrophy, Charcot-Marie-Tooth disease, Brachyolmia (autosomal dominant type), Familial Digital arthropathy with brachydactyly	AD	60	76
TTC21B	Short-rib thoracic dysplasia, Nephronophthisis, Asphyxiating thoracic dysplasia (ATD; Jeune)	AR	17	53
TWIST1	Saethre-Chotzen syndrome, Robinow-Sorauf syndrome, Craniosynostosis	AD	20	203
TYROBP	Nasu-Hakola disease, Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy	AR	8	14
VDR	Vitamin D-dependent rickets	AD/AR	17	65
VIPAS39	Arthrogryposis, renal dysfunction, and cholestasis 2	AR	8	13
WDR19	Retinitis pigmentosa, Nephronophthisis, Short -rib thoracic dysplasia with or without polydactyly, Senior-Loken syndrome, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2, Asphyxiating thoracic dysplasia (ATD; Jeune)	AD/AR	30	28
WDR34	Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune)	AR	16	15
WDR35	Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2, Short rib-polydactyly syndrome type 5	AR	26	28
WDR60	Short-rib thoracic dysplasia 8 with or without polydactyly	AR	10	5
WISP3	Arthropathy, progressive pseudorheumatoid, of childhood, Spondyloepiphyseal dysplasia tarda with progressive arthropathy	AR	16	69
WNT1	Osteoprosis, autosomal dominant, Osteogenesis imperfecta, type XV	AD/AR	8	27
WNT5A	Robinow syndrome	AD	8	10
WNT7A	Ulna and fibula, absence of, with severe limb deficiency (Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome), Fuhrmann syndrome	AR	6	11
XRCC2	Hereditary breast cancer	AD/AR	10	20
XRCC4	Short stature, microcephaly, and endocrine dysfunction	AR	9	11
XYLT1	Desbuquois dysplasia 2	AR	10	16

Non-coding variants covered by the panel

Gene	Genomic location HG19	HGVS	RefSeq	RS-number
ALPL	Chr1:21835920	c.-195C>T	NM_000478.4
ANKH	Chr5:14871567	c.-11C>T	NM_054027.4
BCS1L	Chr2:219524871	c.-147A>G	NM_004328.4
BRCA2	Chr13:32889805	c.-40+1G>A	NM_000059.3
BRCA2	Chr13:32953872	c.8954-15T>G	NM_000059.3
BRCA2	Chr13:32971007	c.9502-28A>G	NM_000059.3	rs397508059
BRIP1	Chr17:59858864	c.1629-498A>T	NM_032043.2
CANT1	Chr17:77005745	c.-342+1G>A	NM_138793.3
CASR	Chr3:121994640	c.1378-19A>C	NM_001178065.1
CDKN1C	Chr11:2905209	c.*5+20G>T	NM_000076.2	rs760540648
CLCN7	Chr16:1506057	c.916+57A>T	NM_001287.5
COL11A1	Chr1:103488576	c.1027-24A>G	NM_080629.2
COL11A1	Chr1:103386637	c.3744+437T>G	NM_080629.2
COL1A1	Chr17:48272201	c.1354-12G>A	NM_000088.3	rs72648337
COL1A1	Chr17:48268147	c.2343+31T>A	NM_000088.3
COL1A1	Chr17:48267611	c.2451+77C>T	NM_000088.3	rs72651665
COL1A1	Chr17:48267594	c.2451+94G>T	NM_000088.3
COL1A1	Chr17:48273742	c.904-14G>A	NM_000088.3
COL2A1	Chr12:48379984	c.1527+135G>A	NM_001844.4
COL5A1	Chr9:137680989	c.2647-12A>G	NM_000093.4
COL5A1	Chr9:137726806	c.5137-11T>A	NM_000093.4	rs183495554
CRTAP	Chr3:33160815	c.472-1021C>G	NM_006371.4	rs72659360
CUL7	Chr6:43010511	c.3897+29G>A	NM_001168370.1
DYNC2H1	Chr11:103019205	c.2819-14A>G	NM_001080463.1	rs781091611
EFNB1	ChrX:68049525	c.-95T>C/G	NM_004429.4
EP300	Chr22:41537040	c.1879-12A>G	NM_001429.3
EVC	Chr4:5749725	c.940-150T>G	NM_153717.2
FANCA	Chr16:89849346	c.1567-20A>G	NM_000135.2	rs775154397
FANCA	Chr16:89836805	c.2223-138A>G	NM_000135.2
FANCA	Chr16:89836111	c.2504+134A>G	NM_000135.2
FANCA	Chr16:89831215	c.2778+83C>G	NM_000135.2	rs750997715
FANCA	Chr16:89818822	c.2982-192A>G	NM_000135.2
FANCA	Chr16:89816056	c.3239+82T>G	NM_000135.2
FANCA	Chr16:89864654	c.893+920C>A	NM_000135.2
FANCD2	Chr3:10083186	c.696-121C>G	NM_033084.3
FANCI	Chr15:89825208	c.1583+142C>T	NM_001113378.1
FBN1	Chr15:48739106	c.5672-87A>G	NM_000138.4
FBN1	Chr15:48739107	c.5672-88A>G	NM_000138.4
FBN1	Chr15:48720682	c.6872-14A>G	NM_000138.4
FBN1	Chr15:48721629	c.6872-961A>G	NM_000138.4
FBN1	Chr15:48707358	c.8051+375G>T	NM_000138.4
FBN1	Chr15:48818478	c.863-26C>T	NM_000138.4
FBN2	Chr5:127671284	c.3725-15A>G	NM_001999.3
FBN2	Chr5:127670560	c.3974-24A>C	NM_001999.3
FBN2	Chr5:127670562	c.3974-26T>G	NM_001999.3
FGFR2	Chr10:123099960	c.*139411C>T	.
GHR	Chr5:42689204	c.287+83G>T	NM_001242399.2
GHR	Chr5:42700896	c.639+792A>G	NM_001242399.2
GHRHR	Chr7:31003560	c.-124A>C	NM_000823.3
GNAS	Chr20:57478716	c.2242-11A>G	NM_080425.2
HSPG2	Chr1:22211006	c.1654+15G>A	NM_005529.5
HSPG2	Chr1:22215993	c.574+481C>T	NM_005529.5
IDS	ChrX:148564764	c.1181-15C>A	NM_000202.5
IDS	ChrX:148578704	c.709-657G>A	NM_000202.5
IFITM5	Chr11:299504	c.-14C>T	NM_001025295.2	rs587776916	Explain almost all cases of OI type V	PMID 23240094
LMNA	Chr1:156107037	c.1608+14G>A	NM_170707.3
LMNA	Chr1:156107433	c.1609-12T>G	NM_170707.3	rs267607582
LMNA	Chr1:156105681	c.937-11C>G	NM_170707.3	rs267607645
LZTR1	Chr22:21340117	c.264-13G>A	NM_006767.3	rs587777176
NF1	Chr17:29422056	c.-272G>A	NM_001042492.2
NF1	Chr17:29422055	c.-273A>C	NM_001042492.2
NF1	Chr17:29530107	c.1260+1604A>G	NM_001042492.2
NF1	Chr17:29533239	c.1261-19G>A	NM_001042492.2
NF1	Chr17:29534143	c.1392+754T>G	NM_001042492.2
NF1	Chr17:29488136	c.288+2025T>G	NM_001042492.2
NF1	Chr17:29577082	c.4110+945A>G	NM_001042492.2
NF1	Chr17:29580296	c.4173+278A>G	NM_001042492.2
NF1	Chr17:29654479	c.5269-38A>G	NM_001042492.2
NF1	Chr17:29656858	c.5610-456G>T	NM_001042492.2
NF1	Chr17:29508428	c.587-12T>A	NM_001042492.2
NF1	Chr17:29508426	c.587-14T>A	NM_001042492.2
NF1	Chr17:29664375	c.6428-11T>G	NM_001042492.2
NF1	Chr17:29664618	c.6642+18A>G	NM_001042492.2
NF1	Chr17:29676126	c.7190-12T>A	NM_001042492.2
NF1	Chr17:29685481	c.7971-17C>G	NM_001042492.2
NF1	Chr17:29685177	c.7971-321C>G	NM_001042492.2
NF1	Chr17:29685665	c.8113+25A>T	NM_001042492.2
NF1	Chr17:29510334	c.888+651T>A	NM_001042492.2
NF1	Chr17:29510427	c.888+744A>G	NM_001042492.2
NF1	Chr17:29510472	c.888+789A>G	NM_001042492.2
NIPBL	Chr5:36953718	c.-79-2A>G	NM_133433.3
NIPBL	Chr5:36877266	c.-94C>T	NM_133433.3
NIPBL	Chr5:37022138	c.5329-15A>G	NM_133433.3	rs587783968
PALB2	Chr16:23649285	c.109-12T>A	NM_024675.3	rs774949203
PHEX	ChrX:22266301	c.*231A>G	NM_000444.4
PHEX	ChrX:22237137	c.1701-16T>A	NM_000444.4
PHEX	ChrX:22113485	c.849+1268G>T	NM_000444.4
PITX2	Chr4:111539855	c.412-11A>G	NM_000325.5
PLS3	ChrX:114856534	c.74-24T>A	NM_005032.5
POR	Chr7:75544501	c.-5+4A>G	NM_000941.2
PRKAR1A	Chr17:66508689	c.-7G>A	NM_002734.4
PRKAR1A	Chr17:66508599	c.-97G>A	NM_002734.4
PRKAR1A	Chr17:66521878	c.550-17T>A	NM_002734.4
PRKAR1A	Chr17:66523964	c.709-7_709-2delTTTTTA	NM_002734.4	rs281864801
PROP1	Chr5:177420059	c.343-11C>G	NM_006261.4
PTH1R	Chr3:46942604	c.1049+29C>T	NM_000316.2
PTPN11	Chr12:112915602	c.934-59T>A	NM_002834.3
RMRP	Chr9:35657745		NR_003051.3	rs377349293
RMRP	Chr9:35657746		NR_003051.3	rs551655682
SERPINF1	Chr17:1679209	c.787-617G>A	NM_002615.5
STAMBP	Chr2:74077998	c.1005+358A>G	NM_006463.4
TBX5	Chr12:114704515	c.*88822C>A	NM_000192.3	rs141875471
TCF12	Chr15:57554272	c.1468-20T>A	NM_207036.1
TCIRG1	Chr11:67806587	c.-5+1G>C/T	NM_006019.3
TCIRG1	Chr11:67816893	c.1887+132T>C	NM_006019.3
TCIRG1	Chr11:67816903	c.1887+142T>A	NM_006019.3
TCIRG1	Chr11:67816907	c.1887+146G>A	NM_006019.3
TCIRG1	Chr11:67816910	c.1887+149C>T	NM_006019.3
TGFBR2	Chr3:30648317	c.-59C>T	NM_001024847.2
TRIM37	Chr17:57106096	c.1949-12A>G	NM_015294.3
TRPS1	Chr8:116427335	c.2824-23T>G	NM_014112.2
WDR35	Chr2:20182313	c.143-18T>A	NM_001006657.1
WDR35	Chr2:20151929	c.1434-684G>T	NM_001006657.1
WISP3	Chr6:112381431	c.103-763G>T	NM_198239.1
WISP3	Chr6:112386227	c.643+27C>G	NM_198239.1	rs200472841
XRCC4	Chr5:82400728	c.-10-1G>T	NM_022406.2	rs869320678

Genes added

Genes removed

The strengths of this test include:

CAP and ISO-15189 accreditations covering all operations at GHC 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 GHC 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. GHC 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.