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Comprehensive Skeletal Dysplasias and Disorders Panel

246 gene panel that includes assessment of non-coding variants

Ideal for patients with a clinical suspicion of disorders involving the skeletal system.

Analysis methods Availability Number of genes Test code CPT codes
4 weeks 246 GHC0121 SEQ 81406
SEQ 81407
SEQ 81408
DEL/DUP 81479


ICD codes
Commonly used ICD-10 code(s) when ordering the Comprehensive Skeletal Dysplasias and Disorders Panel

ICD-10 Disease
Q89.7 Skeletal dysplasia and disorders

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 skeletal disorders including common and rare skeletal dysplasias (eg. achondroplasia, COL2A1 related dysplasias, diastrophic dysplasia, various types of spondylo-metaphyseal dysplasias), various ciliopathies with skeletal involvement (eg. short rib-polydactylies, asphyxiating thoracic dysplasia dysplasias and Ellis-van Creveld syndrome), various subtypes of osteogenesis imperfecta, campomelic dysplasia, slender bone dysplasias, dysplasias with multiple joint dislocations, chondrodysplasia punctata group of disorders, neonatal osteosclerotic dysplasias, osteopetrosis and related disorders, abnormal mineralization group of disorders (eg hypopohosphatasia), osteolysis group of disorders, disorders with disorganized development of skeletal components, overgrowth syndromes with skeletal involvement, craniosynostosis syndromes, dysostoses with predominant craniofacial involvement, dysostoses with predominant vertebral involvement, patellar dysostoses, brachydactylies, some disorders with limb hypoplasia-reduction defects, ectrodactyly with and without other manifestations, polydactyly-syndactyly-triphalangism group of disorders, and disorders with defects in joint formation and synostoses.

Panel Content

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

Gene Associated phenotypes Inheritance ClinVar HGMD
ACANSpondyloepimetaphyseal dysplasia, aggrecan type, Spondyloepiphyseal dysplasia, Kimberley type, Osteochondritis dissecans, short stature, and early-onset osteoarthritisAD/AR1830
ACP5Spondyloenchondrodysplasia with immune dysregulationAR1126
ACVR1Fibrodysplasia ossificans progressivaAD1419
ADAMTS10Weill-Marchesani syndromeAR813
ADAMTS17Weill-Marchesani-like syndromeAR67
ADAMTSL2Geleophysic dysplasiaAR828
AGPSRhizomelic chondrodysplasia punctata type 3AR48
AIFM1Deafness, Combined oxidative phosphorylation deficiency 6, Cowchock syndromeXL2729
AKT1Proteus syndrome, Cowden syndromeAD56
ALPLOdontohypophosphatasia, Hypophosphatasia perinatal lethal, infantile, juvenile and adult formsAD/AR61290
ALX3Frontonasal dysplasia type 1AR77
ALX4Frontonasal dysplasia type 2, Parietal foraminaAD/AR1523
AMER1Osteopathia striata with cranial sclerosisXL1438
ANKHCalcium pyrophosphate deposition disease (familial chondrocalcinosis type 2), Craniometaphyseal dysplasia autosomal dominant typeAD1220
ANKRD11KBG syndromeAD119122
ANO5Gnathodiaphyseal dysplasia, LGMD2L and distal MMD3 muscular dystrophiesAD/AR60115
ARHGAP31Adams-Oliver syndromeAD24
ARSBMucopolysaccharidosis (Maroteaux-Lamy)AR27199
ARSEChondrodysplasia punctata X-linked recessive, brachytelephalangic type (CDPX1)XL2146
ATP6V0A2Cutis laxa, Wrinkly skin syndromeAR1654
B3GALT6Spondyloepimetaphyseal dysplasia with joint laxity, Ehlers-Danlos syndromeAR1726
B3GAT3Multiple joint dislocations, short stature, craniofacial dysmorphism, and congenital heart defectsAR513
B4GALT7Ehlers-Danlos syndrome, progeroid formAR99
BGNSpondyloepimetaphyseal dysplasia, X-linked, Meester-Loeys syndromeXL87
BHLHA9Syndactyly Malik-Percin type, mesoaxial synostotic, with phalangeal reduction, Split hand-foot malformation with long bone deficiency (SHFLD3), Gollop-WolfgangAR437
BMP1Osteogenesis imperfectaAR715
BMP2Brachydactyly type A2AD528
BMPR1BAcromesomelic dysplasia, Demirhan, Brachydactyly C/Symphalangism-like pheno, Brachydactyly type A2AD/AR1216
CA2Osteopetrosis, with renal tubular acidosisAR931
CANT1Desbuquois dysplasiaAR2028
CASRHypocalcemia, Neonatal hyperparathyroidism, Familial Hypocalciuric hypercalcemia with transient Neonatal hyperparathyroidismAD/AR103393
CDC6Meier-Gorlin syndrome (Ear-patella-short stature syndrome)AR22
CDC45Meier-Gorlin syndrome 7AR1019
CDKN1CBeckwith-Wiedemann syndrome, IMAGE syndromeAD2881
CDT1Meier-Gorlin syndrome (Ear-patella-short stature syndrome)AR611
CHST3Spondyloepiphyseal dysplasia with congenital joint dislocations (recessive Larsen syndrome)AR1936
CHST14Ehlers-Danlos syndrome, musculocontracturalAR1421
CHSY1Temtamy preaxial brachydactyly syndromeAR611
CKAP2LFilippi syndromeAR77
CLCN5Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis, Hypophosphatemic rickets,, Nephrolithiasis, I, Dent diseaseXL45267
COL1A1Ehlers-Danlos syndrome, Caffey disease, Osteogenesis imperfecta type 1, Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4AD290943
COL1A2Ehlers-Danlos syndrome, cardiac valvular form, Osteogenesis imperfecta type 1, Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4AD/AR162496
COL2A1Avascular 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 1AD166544
COL9A1Stickler syndrome recessive type, Multiple epiphyseal dysplasia type 6 (EDM6)AR95
COL9A2Stickler syndrome, Multiple epiphyseal dysplasia type 2 (EDM2)AD/AR712
COL9A3Multiple epihyseal dysplasia type 3 (EDM3)AD/AR1015
COL10A1Metaphyseal chondrodysplasia, SchmidAD2151
COL11A1Marshall syndrome, Fibrochondrogenesis, Stickler syndrome type 2AD/AR3086
COL11A2Weissenbacher-Zweymuller syndrome, Deafness, Otospondylomegaepiphyseal dysplasia, Fibrochondrogenesis, Stickler syndrome type 3 (non-ocular)AD/AR2855
COMPPseudoachondroplasia, Multiple ephiphyseal dysplasiaAD43184
CREBBPRubinstein-Taybi syndromeAD156348
CRTAPOsteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4AR1228
CSPP1Jeune asphyxiating thoracic dystrophy, Joubert syndromeAR2727
CUL73-M syndrome, Yakut short stature syndromeAR2680
CYP27B1Vitamin D-dependent ricketsAR2373
DDR2Spondylometaepiphyseal dysplasia, short limb-hand typeAR117
DLL3Spondylocostal dysostosisAR1123
DLL4Adams-Oliver syndromeAD1012
DLX3Amelogenesis imperfecta, Trichodontoosseous syndromeAD56
DMP1Hypophosphatemic ricketsAR510
DOCK6Adams-Oliver syndromeAR2119
DVL1Robinow syndromeAD1617
DYMDyggve-Melchior-Clausen dysplasia, Smith-McCort dysplasiaAR2134
DYNC2H1Short -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/Digenic144109
EBPChondrodysplasia punctata, Male EBP disorder with neurologic defects (MEND)XL4390
EFNB1Craniofrontonasal dysplasiaXL27115
EFTUD2Mandibulofacial dysostosis with microcephaly, Esophageal atresia, syndromicAD4393
EIF2AK3SED, Wolcott-Rallison typeAR978
ENAMAmelogenesis imperfectaAR818
ENPP1Arterial calcification, Hypophosphatemic ricketsAR2068
EOGTAdams-Oliver syndromeAR35
EP300Rubinstein-Taybi syndromeAD5791
ESCO2SC phocomelia syndrome, Roberts syndromeAR2930
EVCWeyers acrofacial dysostosis, Ellis-van Creveld syndromeAD/AR2280
EVC2Ellis-van Creveld syndrome, Weyers acrodental dysostosisAD/AR3467
EXT1Multiple cartilagenious exostoses 1AD67497
EXT2Multiple cartilagenious exostoses 2AD32242
EXTL3Immunoskeletal dysplasia with neurodevelopmental abnormalities (ISDNA)AR47
EZH2Weaver syndromeAD2940
FAM20AAmelogenesis imperfecta (Enamel-renal syndrome)AR1741
FAM20CHypophosphatemia, hyperphosphaturia, dental anomalies, intracerebral calcifications and osteosclerosis (Raine syndrome)AR1323
FAM83HAmelogenesis imperfectaAD1429
FAM111AKenny-Caffey syndrome, type 2AD49
FANCBFanconi anemiaXL1020
FANCCFanconi anemiaAR7058
FBN1MASS syndrome, Marfan syndrome, Acromicric dysplasia, Geleophysic dysplasiaAD9192548
FBN2Congenital contractural arachnodactyly (Beals syndrome)AD4595
FGF23Tumoral calcinosis, hyperphosphatemic, Hypophosphatemic ricketsAD/AR1016
FGFR1Pfeiffer syndrome, Trigonocephaly, Hypogonadotropic hypogonadism, Osteoglophonic Dwarfism - Craniostenosis, Hartsfield syndromeAD/Digenic/Multigenic69241
FGFR2Apert 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 dysplasiaAD93150
FGFR3Lacrimoauriculodentodigital 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, SADDANAD/AR5372
FKBP10Bruck syndrome type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4AR2037
FLNAFrontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defectsXL119235
FLNBLarsen syndrome (dominant), Atelosteogenesis type 1, Atelosteogenesis type 3, Spondylo-carpal-tarsal dyspasiaAD/AR41103
GALNT3Tumoral calcinosis, hyperphosphatemicAR1634
GDF5Multiple synostoses syndrome, Fibular hypoplasia and complex brachydactyly, Acromesomelic dysplasia, Hunter-Thompson, Symphalangism, proximal, Chondrodysplasia, Brachydactyly type A2, Brachydactyly type C, Grebe dysplasiaAD/AR2350
GJA1Oculodentodigital dysplasia mild type, Oculodentodigital dysplasia severe type, Syndactyly type 3AD/AR32106
GLI3Acrocallosal syndrome, Pallister-Hall syndrome, Grieg cephalopolysndactyly syndrome, Postaxial polydactyly type A, Preaxial polydactyly type 3, Preaxial polydactyly type 4AD63229
GNASMcCune-Albright syndrome, Progressive osseous heteroplasia, Pseudohypoparathyroidism, Albright hereditary osteodystrophyAD62265
GNPATRhizomelic chondrodysplasia punctata, rhizomelicAR814
GPC6Omodysplasia 1AR119
HDAC8Cornelia de Lange syndromeXL3344
HOXA13Hand-foot-uterus syndrome, Hand-foot-genital syndrome, Guttmacher syndromeAD824
HOXD13Brachydactyly-syndactyly syndrome, Synopolydactyly, Syndactyly, Synopolydactyly with clefting, Brachydactyly type DAD/AR1840
HSPG2Schwartz-Jampel syndrome, Dyssegmental dysplasia Silverman-Handmaker type, Dyssegmental dysplasia Rolland-Desbuquis typeAD/AR1656
IFT43Cranioectodermal dysplasia 3AR46
IFT80Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune)AR117
IFT122Sensenbrenner syndrome, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2AR1121
IFT140Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune)AR3754
IFT172Retinitis pigmentosa, Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune)AR2123
IHHAcrocapitofemoral dysplasia, Brachydactyly, Syndactyly type LuekenAD/AR1220
IMPAD1Chondrodysplasia with joint dislocations, GPAPP typeAR55
KAT6BOhdo syndrome, SBBYS variant, Genitopatellar syndromeAD3862
KIF7Acrocallosal syndrome, Hydrolethalus syndrome, Al-Gazali-Bakalinova syndrome, Joubert syndromeAR/Digenic2340
KIF22Spondyloepimetaphyseal dysplasia with joint laxity, type 2AD44
KMT2AWiedemann-Steiner syndromeAD10783
LBRPelger-Huet anomaly, Reynolds syndrome, Greenberg/HEM skeletal dysplasia, Hydrops-ectopic calcification-moth-eaten skeletal dysplasiaAD1823
LEMD3Buschke-Ollendorff syndrome, OsteopoikilosisAD1131
LIFRStuve-Wiedemann dysplasia, Schwartz-Jampel type 2 syndromeAR1132
LMNAHeart-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 typeAD/AR231553
LMX1BNail-patella syndromeAD26192
LONP1Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies (CODAS) syndromeAR716
LRP4Cenani-Lenz syndactyly syndrome, Sclerosteosis, Myasthenic syndrome, congenitalAD/AR1324
LRP5*Van Buchem disease, Osteoporosis-pseudoglioma syndrome, Hyperostosis, endosteal, Osteosclerosis, Exudative vitreoretinopathy, Osteopetrosis late-onset form type 1, LRP5 primary osteoporosisAD/AR/Digenic55188
LTBP2Weill-Marchesani syndrome, Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, Glaucoma, primary congenitalAR2126
LTBP3Dental anomalies and short statureAR1510
MAFBMulticentric carpotarsal osteolysisAD1322
MATN3Spondyloepimetaphyseal dysplasia Matrilin type, Multiple epiphyseal dysplasia type 5 (EDM5)AD/AR824
MESP2Spondylocostal dysostosis 2, autosomal recessiveAR75
MGPKeutel syndromeAR57
MMP2Torg-Winchester syndrome, Multicentric osteolysis, nodulosis, and arthropathyAR822
MMP9Metaphyseal anadysplasiaAR16
MMP13Metaphyseal anadysplasia 1, Metaphyseal dysplasia, Spahr type, Spondyloepimetaphyseal dysplasia, Missouri typeAD/AR76
MSX2*Parietal foramina, Parietal foramina with cleidocranial dysplasia, Craniosynostosis Boston typeAD925
MYCNFeingold syndromeAD2540
NANSSpondyloepimetaphyseal dysplasiam Genevieve typeAR812
NEK1Short -rib thoracic dysplasia with or without polydactyly, SRPS type 2 (Majewski)AR/Digenic2120
NF1*Watson syndrome, Neurofibromatosis, Neurofibromatosis-Noonan syndromeAD8102703
NIPBLCornelia de Lange syndromeAD290419
NKX3-2Spondylo-megaepiphyseal-metaphyseal dysplasiaAR34
NOGTarsal-carpal coalition syndrome, Multiple synostosis syndrome, Stapes ankylosis with broad thumb and toes (Teunissen-Cremers syndrome), Symphalangism, proximal, Brachydactyly type B2AD2062
NOTCH2Alagille syndrome, Hajdu-Cheney syndromeAD3563
NPR2Acromesomelic dysplasia type Maroteaux, Epiphyseal chondrodysplasia, Miura, Short stature with nonspecific skeletal abnormalitiesAD/AR3067
NSD1Sotos syndrome, Weaver syndrome, Beckwith-Wiedemann syndromeAD303515
NSDHLCongenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome), CK syndromeXL1528
OBSL13-M syndromeAR1333
ORC1Meier-Gorlin syndrome (Ear-patella-short stature syndrome)AR99
ORC4Meier-Gorlin syndrome (Ear-patella-short stature syndrome)AR226
ORC6Meier-Gorlin syndrome (Ear-patella-short stature syndrome)AR76
OSTM1Osteopetrosis, autosomal recessive 5AR59
P3H1Osteogenesis imperfectaAR1555
PAPSS2Brachyolmia 4 with mild epiphyseal and metaphyseal changes, SEMD PAPPS2 typeAR1119
PCNTMicrocephalic osteodysplastic primordial dwarfismAR4884
PCYT1ASpondylometaphyseal dysplasia with cone-rod dystrophyAR1220
PDE4DAcrodysostosis 2, with or without hormone resistanceAD1436
PEX7Refsum disease, Rhizomelic CDP type 1AR3752
PGM3Immunodeficiency 23AR1314
PHEXHypophosphatemic ricketsXL262428
PIK3CACowden syndrome, CLOVESAD8653
PLOD2Bruck syndrome, Osteogenesis imperfecta type 3AR817
PLS3Osteoporosis and osteoporotic fracturesXL114
POLR1CTreacher Collins syndromeAR1620
POLR1DTreacher Collins syndromeAD/AR826
PORDisordered steroidogenesis due to cytochrome p450 oxidoreductase deficiency, Antley-Bixler syndromeAR1268
PPIBOsteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4AR813
PRKAR1AMyxoma, intracardiac, Acrodysostosis, Pigmented nodular adrenocortical disease, Carney complexAD66180
PTDSS1Lenz-Majewski hyperostotic dwarfismAD55
PTH1RMetaphyseal chondrodysplasia Jansen type, Failure of tooth eruption, Eiken dysplasia, Blomstrand dysplasiaAD/AR1340
PTHLHBrachydactyly, type E2AD517
PTPN11Noonan syndrome, MetachondromatosisAD128139
PYCR1Cutis laxa AR type 2BAR1938
RAB33BDyggve-Melchior-Clausen syndrome, Smith-McCort dysplasia 2AR67
RAD21Cornelia de Lange syndrome 4AD911
RBPJAdams-Oliver syndromeAD45
RECQL4Baller-Gerold syndrome, RAPADILINO syndrome, Rothmund-Thomson syndromeAR53100
RMRPCartilage-hair hypoplasia, Metaphyseal dysplasia without hypotrichosis, Anauxetic dysplasiaAR34123
RNU4ATACRoifman syndrome, Microcephalic osteodysplastic primordial dwarfism type 1, Microcephalic osteodysplastic primordial dwarfism type 3AR1521
ROR2Robinow syndrome recessive type, Brachydactyly type BAD/AR1940
RUNX2Cleidocranial dysplasia, Metaphyseal dysplasia with maxillary hypoplasiaAD21213
SBDSAplastic anemia, Shwachman-Diamond syndrome, Severe spondylometaphyseal dysplasiaAD/AR2190
SERPINF1Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4AR935
SERPINH1Osteogenesis imperfecta type 3AR33
SETBP1Mental retardation, autosomal dominant 29, Schinzel-Giedion midface retraction syndromeAD2140
SF3B4Acrofacial dysostosis 1, NagerAD2736
SH3PXD2BFrank-ter Haar syndromeAR918
SHOXLeri-Weill dyschondrosteosis, Langer mesomelic dysplasia, Short statureXL/PAR25426
SKIShprintzen-Goldberg syndromeAD1721
SLC26A2Diastrophic dysplasia, Atelosteogenesis type 2, De la Chapelle dysplasia, Recessive Multiple Epiphyseal dysplasia, Achondrogenesis type 1BAR5550
SLC29A3Histiocytosis-lymphadenopathy plus syndrome, DysosteosclerosisAR1624
SLC34A3Hypophosphatemic rickets with hypercalciuriaAR2236
SLC35D1Schneckenbecken dysplasiaAR77
SLC39A13Spondylodysplastic Ehlers-Danlos syndromeAR28
SLCO2A1Hypertrophic osteoarthropathyAD/AR1371
SMAD3Aneurysms-osteoarthritis syndrome, Loeys-Dietz syndromeAD4355
SMAD4Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Polyposis, juvenile intestinal, Myhre dysplasia, Hereditary hemorrhagic telangiectasiaAD162141
SMARCAL1Schimke immunoosseous dysplasiaAR1788
SMC1ACornelia de Lange syndromeXL5687
SMC3Cornelia de Lange syndromeAD2120
SNX10Osteopetrosis, autosomal recessive 8AR313
SOSTCraniodiaphyseal dysplasia, autosomal dominant, Sclerosteosis 1, van Buchem diseaseAD/AR614
SOX9Campomelic dysplasia, 46,XY sex reversal, Brachydactyly with anonychia (Cooks syndrome)AD44141
SP7Osteogenesis imperfecta, type XIIAR11
STAMBPMicrocephaly-capillary malformation syndromeAR1419
TBX3Ulnar-Mammary syndromeAD620
TBX4Small patella syndromeAD530
TBX6Spondylocostal dysostosis 5AD934
TBX15Cousin syndromeAR23
TCIRG1Osteopetrosis, severe neonatal or infantile forms (OPTB1)AD/AR14130
TCOF1Treacher Collins syndromeAD42320
TCTN3Orofaciodigital syndrome (Mohr-Majewski syndrome), Joubert syndromeAR910
TGFB1Diaphyseal dysplasia Camurati-EngelmannAD1518
TGFB2Loeys-Dietz syndromeAD3428
TGFB3Loeys-Dietz syndrome (Reinhoff syndrome), Arrhythmogenic right ventricular dysplasiaAD1722
TGFBR1Loeys-Dietz syndromeAD3769
TGFBR2Loeys-Dietz syndromeAD58136
TMEM38BOsteogenesis imperfecta, type XIVAR26
TNFRSF11AFamilial expansile osteolysis, Paget disease of bone, Osteopetrosis, severe neonatal or infantile forms (OPTB1)AD/AR823
TNFRSF11BPaget disease of bone, juvenileAR818
TNFSF11Osteopetrosis, autosomal recessive 2AR35
TP63Rapp-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 syndromeAD55116
TRAPPC2Spondyloepiphyseal dysplasia tardaXL1254
TRIP11Achondrogenesis, type IAAR713
TRPS1Trichorhinophalangeal syndrome type 1, Trichorhinophalangeal syndrome type 3AD59139
TRPV4Metatropic 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 brachydactylyAD6076
TTC21BShort-rib thoracic dysplasia, Nephronophthisis, Asphyxiating thoracic dysplasia (ATD; Jeune)AR1753
TWIST1Saethre-Chotzen syndrome, Robinow-Sorauf syndrome, CraniosynostosisAD20203
TYROBPNasu-Hakola disease, Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathyAR814
VDRVitamin D-dependent ricketsAD/AR1765
VIPAS39Arthrogryposis, renal dysfunction, and cholestasis 2AR813
WDR19Retinitis 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/AR3028
WDR34Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune)AR1615
WDR35Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2, Short rib-polydactyly syndrome type 5AR2628
WDR60Short-rib thoracic dysplasia 8 with or without polydactylyAR105
WISP3Arthropathy, progressive pseudorheumatoid, of childhood, Spondyloepiphyseal dysplasia tarda with progressive arthropathyAR1669
WNT1Osteoprosis, autosomal dominant, Osteogenesis imperfecta, type XVAD/AR827
WNT5ARobinow syndromeAD810
XYLT1Desbuquois dysplasia 2AR1016

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number
IFITM5Chr11:299504c.-14C>TNM_001025295.2rs587776916Explain almost all cases of OI type VPMID 23240094

Panel Update

Genes added

  • ACAN
  • ADAMTS17
  • AIFM1
  • ANKRD11
  • ARSB
  • B3GAT3
  • BGN
  • CDC45
  • CHSY1
  • CKAP2L
  • DDR2
  • DMP1
  • EXTL3
  • FAM111A
  • GALNT3
  • GPC6
  • IDS
  • IFT43
  • IMPAD1
  • INPPL1
  • KIF22
  • KMT2A
  • LONP1
  • LTBP3
  • MAFB
  • MESP2
  • MGP
  • MMP13
  • MMP2
  • MYCN
  • NANS
  • NKX3-2
  • OSTM1
  • PCYT1A
  • PDE4D
  • PGM3
  • PLS3
  • POLR1D
  • PTDSS1
  • RAB33B
  • RAD21
  • SETBP1
  • SH3BP2
  • SH3PXD2B
  • SLC35D1
  • SNX10
  • SOST
  • SP7
  • TBX15
  • TBX4
  • TBX6
  • TMEM38B
  • TNFSF11
  • TRIP11
  • VIPAS39
  • WDR60
  • WNT1
  • XYLT1

Genes removed


Test strength and Limitations

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.

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. 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.

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.