Comprehensive Skeletal Dysplasias and Disorders Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: MA3301

The Blueprint Genetics Comprehensive Skeletal Dysplasias and Disorders Panel is a 186-gene panel.

This panel is ideal for:

  • Patients with a clinical suspicion of skeletal dysplasia and disorders

This panel includes a pathogenic intronic variant that is often missed by exome sequencing: IFITM5c.-14C>T (rs587776916), which practically accounts almost all cases of osteogenesis imperfecta type V (PMID 23240094). Currently, other regions of IFITM5 gene are not covered.

Due to one or more regions of segmental duplication, this panel has reduced sensitivity to detect variants in regions of 11 of the 186 genes on this panel (for a complete list of the affected genes, please refer to the Gene Set Description list for this panel). This is not suspected to significantly decrease the sensitivity of the panel overall. If you suspect one of the affected genes is responsible for the phenotype in your patient, please contact our Support Team for additional information.

The genes on this panel are included in the Comprehensive Skeletal / Malformation Syndrome Panel.

Inherited skeletal disorders are known to be difficult to subtype and divide into categories. This panel covers vast majority of the genes listed in the Nosology and Classification of Genetic Skeletal Disorders 2015 Revision (PMID: 26394607). This panel covers broad spectrum of skeletal disorders including the common and rare skeletal dysplasias (eg. achondroplasia, COL2A1 related dysplasias, diastrophic dysplasia, various types of spondylo-metaphyeal dysplasias), various ciliopathies with major 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. This Panel is part of the Comprehensive Skeletal / Malformation Syndrome Panel Panel.

This panel includes also a pathogenic intronic variant that is often missed by exome sequencing: IFITM5 c.-14C>T (rs587776916), which practically accounts almost all cases of osteogenesis imperfecta type V (PMID 23240094). Currently, other regions of IFITM5 gene are not yet covered.

About Comprehensive Skeletal Dysplasias and Disorders

This panel covers broad spectrum of skeletal dysplasias, metabolic bone disorders, dysostoses and skeletal malformation and/or reduction syndromes. Genetic diagnostics in these group of disorders is the most efficient way to establish the diagnosis in the molecular level. Moreover, detection of causative mutation(s) establishes the inheritance mode in the family and enables the genetic counseling.

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

Genes in the Comprehensive Skeletal Dysplasias and Disorders Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ACP5 Spondyloenchondrodysplasia with immune dysregulation AR 10 26
ACVR1 Fibrodysplasia ossificans progressiva AD 14 18
ADAMTS10 Weill-Marchesani syndrome AR 8 13
ADAMTSL2 Geleophysic dysplasia AR 8 27
AGPS Rhizomelic chondrodysplasia punctata type 3 AR 4 8
AKT1 Proteus syndrome, Cowden syndrome AD 5 6
ALPL Odontohypophosphatasia, Hypophosphatasia perinatal lethal, infantile, juvenile and adult forms AD/AR 55 288
ALX3 Frontonasal dysplasia type 1 AR 7 7
ALX4 Frontonasal dysplasia type 2, Parietal foramina AD/AR 15 22
AMER1 Osteopathia striata with cranial sclerosis XL 13 36
ANKH Calcium pyrophosphate deposition disease (familial chondrocalcinosis type 2), Craniometaphyseal dysplasia autosomal dominant type AD 12 20
ANO5 Gnathodiaphyseal dysplasia, LGMD2L and distal MMD3 muscular dystrophies AD/AR 49 115
ARHGAP31 Adams-Oliver syndrome AD 2 4
ARSE* Chondrodysplasia punctata X-linked recessive, brachytelephalangic type (CDPX1) XL 19 46
ATP6V0A2 Cutis laxa, Wrinkly skin syndrome AR 16 53
B3GALT6 Spondyloepimetaphyseal dysplasia with joint laxity, Ehlers-Danlos syndrome AR 15 25
B4GALT7 Ehlers-Danlos syndrome, progeroid form AR 9 8
BHLHA9 Syndactyly Malik-Percin type, mesoaxial synostotic, with phalangeal reduction, Split hand-foot malformation with long bone deficiency (SHFLD3), Gollop-Wolfgang AR 4 29
BMP1 Osteogenesis imperfecta AR 7 15
BMP2 Brachydactyly type A2 AD 1 19
BMPR1B Acromesomelic dysplasia, Demirhan, Brachydactyly C/Symphalangism-like pheno, Brachydactyly type A2 AD/AR 11 16
CA2 Osteopetrosis, with renal tubular acidosis AR 8 30
CANT1 Desbuquois dysplasia AR 18 27
CASR Hypocalcemia, Neonatal hyperparathyroidism, Familial Hypocalciuric hypercalcemia with transient Neonatal hyperparathyroidism AD/AR 95 392
CDC6 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 2
CDKN1C Beckwith-Wiedemann syndrome, IMAGE syndrome AD 24 81
CDT1 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 6 10
CHST3 Spondyloepiphyseal dysplasia with congenital joint dislocations (recessive Larsen syndrome) AR 15 36
CHST14 Ehlers-Danlos syndrome, musculocontractural AR 13 21
CLCN5 Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis, Hypophosphatemic rickets,, Nephrolithiasis, I, Dent disease XL 40 263
CLCN7 Osteopetrosis AD/AR 11 90
COL1A1 Ehlers-Danlos syndrome, Caffey disease, Osteogenesis imperfecta type 1, Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4 AD 212 929
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 118 490
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 138 541
COL9A1 Stickler syndrome recessive type, Multiple epiphyseal dysplasia type 6 (EDM6) AR 7 5
COL9A2 Stickler syndrome, Multiple epiphyseal dysplasia type 2 (EDM2) AD/AR 7 12
COL9A3 Multiple epihyseal dysplasia type 3 (EDM3) AD/AR 6 15
COL10A1 Metaphyseal chondrodysplasia, Schmid AD 20 50
COL11A1 Marshall syndrome, Fibrochondrogenesis, Stickler syndrome type 2 AD/AR 22 81
COL11A2 Weissenbacher-Zweymuller syndrome, Deafness, Otospondylomegaepiphyseal dysplasia, Fibrochondrogenesis, Stickler syndrome type 3 (non-ocular) AD/AR 23 54
COMP Pseudoachondroplasia, Multiple ephiphyseal dysplasia AD 40 182
CREBBP Rubinstein-Taybi syndrome AD 138 340
CRTAP Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4 AR 11 27
CSPP1 Jeune asphyxiating thoracic dystrophy, Joubert syndrome AR 25 25
CTSK Pycnodysostosis AR 24 54
CUL7 3-M syndrome, Yakut short stature syndrome AR 21 74
CYP27B1 Vitamin D-dependent rickets AR 22 72
DHCR24 Desmosterolosis AR 6 8
DLL3 Spondylocostal dysostosis AR 11 23
DLL4 Adams-Oliver syndrome AD 9 11
DLX3 Amelogenesis imperfecta, Trichodontoosseous syndrome AD 3 6
DOCK6 Adams-Oliver syndrome AR 14 19
DVL1 Robinow syndrome AD 10 13
DYM Dyggve-Melchior-Clausen dysplasia, Smith-McCort dysplasia AR 20 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 46 101
EBP Chondrodysplasia punctata, Male EBP disorder with neurologic defects (MEND) XL 43 89
EFNB1 Craniofrontonasal dysplasia XL 23 115
EFTUD2 Mandibulofacial dysostosis with microcephaly, Esophageal atresia, syndromic AD 33 92
EIF2AK3 SED, Wolcott-Rallison type AR 9 73
ENAM Amelogenesis imperfecta AR 6 18
ENPP1 Arterial calcification, Hypophosphatemic rickets AR 20 67
EOGT Adams-Oliver syndrome AR 3 3
EP300 Rubinstein-Taybi syndrome AD 43 81
ESCO2 SC phocomelia syndrome, Roberts syndrome AR 29 30
EVC Weyers acrofacial dysostosis, Ellis-van Creveld syndrome AD/AR 11 80
EVC2 Ellis-van Creveld syndrome, Weyers acrodental dysostosis AD/AR 26 67
EXT1 Multiple cartilagenious exostoses 1 AD 44 481
EXT2 Multiple cartilagenious exostoses 2 AD 24 229
EZH2 Weaver syndrome AD 26 37
FAM20A Amelogenesis imperfecta (Enamel-renal syndrome) AR 9 41
FAM20C Hypophosphatemia, hyperphosphaturia, dental anomalies, intracerebral calcifications and osteosclerosis (Raine syndrome) AR 13 23
FAM83H Amelogenesis imperfecta AD 13 29
FANCB Fanconi anemia XL 10 18
FANCC Fanconi anemia AR 63 45
FBN1 MASS syndrome, Shprintzen-Goldberg syndrome, Marfan syndrome, Acromicric dysplasia, Geleophysic dysplasia, Weill-Marchesani syndrome AD 711 2070
FBN2 Congenital contractural arachnodactyly (Beals syndrome) AD 35 87
FGF23 Tumoral calcinosis, hyperphosphatemic, Hypophosphatemic rickets AD/AR 10 16
FGFR1 Pfeiffer syndrome, Trigonocephaly, Hypogonadotropic hypogonadism, Osteoglophonic Dwarfism - Craniostenosis, Hartsfield syndrome AD/Digenic/Multigenic 61 239
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 89 149
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 70
FKBP10 Bruck syndrome type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4 AR 18 33
FLNA Frontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defects XL 102 220
FLNB Larsen syndrome (dominant), Atelosteogenesis type 1, Atelosteogenesis type 3, Spondylo-carpal-tarsal dyspasia AD/AR 41 102
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 22 49
GJA1* Oculodentodigital dysplasia mild type, Oculodentodigital dysplasia severe type, Syndactyly type 3 AD 28 105
GLI3 Acrocallosal syndrome, Pallister-Hall syndrome, Grieg cephalopolysndactyly syndrome, Postaxial polydactyly type A, Preaxial polydactyly type 3, Preaxial polydactyly type 4 AD 56 222
GNAS McCune-Albright syndrome, Progressive osseous heteroplasia, Pseudohypoparathyroidism, Albright hereditary osteodystrophy AD 56 256
GNPAT Rhizomelic chondrodysplasia punctata, rhizomelic AR 8 14
HDAC8 Cornelia de Lange syndrome XL 28 44
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 38
HSPG2 Schwartz-Jampel syndrome, Dyssegmental dysplasia Silverman-Handmaker type, Dyssegmental dysplasia Rolland-Desbuquis type AD/AR 15 53
IFT80 Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune) AR 8 7
IFT122* Sensenbrenner syndrome, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2 AR 11 17
IFT140 Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune) AR 19 52
IFT172 Retinitis pigmentosa, Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune) AR 20 23
IHH Acrocapitofemoral dysplasia, Brachydactyly, Syndactyly type Lueken AD/AR 12 20
IKBKG* Incontinentia pigmenti, Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency, Immunodeficiency, Invasive pneumococcal disease, recurrent, isolated, Osteopetrosis with ectodermal dysplasia and immune defect (OLEDAID) XL 43 143
KAT6B Ohdo syndrome, SBBYS variant, Genitopatellar syndrome AD 29 57
KIF7 Acrocallosal syndrome, Hydrolethalus syndrome, Al-Gazali-Bakalinova syndrome, Joubert syndrome AR/Digenic 15 40
LBR Pelger-Huet anomaly, Reynolds syndrome, Greenberg/HEM skeletal dysplasia, Hydrops-ectopic calcification-moth-eaten skeletal dysplasia AD 17 23
LEMD3 Buschke-Ollendorff syndrome, Osteopoikilosis AD 10 29
LIFR Stuve-Wiedemann dysplasia, Schwartz-Jampel type 2 syndrome AR 10 31
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 211 513
LMX1B Nail-patella syndrome AD 23 191
LRP4 Cenani-Lenz syndactyly syndrome, Sclerosteosis, Myasthenic syndrome, congenital AD/AR 12 22
LRP5* Van Buchem disease, Osteoporosis-pseudoglioma syndrome, Hyperostosis, endosteal, Osteosclerosis, Exudative vitreoretinopathy, Osteopetrosis late-onset form type 1, LRP5 primary osteoporosis AD/AR/Digenic 44 170
LTBP2 Weill-Marchesani syndrome, Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, Glaucoma, primary congenital AR 21 25
MATN3 Spondyloepimetaphyseal dysplasia Matrilin type, Multiple epiphyseal dysplasia type 5 (EDM5) AD/AR 8 24
MMP9 Metaphyseal anadysplasia AR 1 4
MSX2* Parietal foramina, Parietal foramina with cleidocranial dysplasia, Craniosynostosis Boston type AD 9 24
NEK1 Short -rib thoracic dysplasia with or without polydactyly, SRPS type 2 (Majewski) AR/Digenic 10 16
NF1* Watson syndrome, Neurofibromatosis, Neurofibromatosis-Noonan syndrome AD 592 2681
NFIX Marshall-Smithsyndrome AD 34 65
NIPBL Cornelia de Lange syndrome AD 268 417
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 61
NOTCH2* Alagille syndrome, Hajdu-Cheney syndrome AD 25 61
NPR2 Acromesomelic dysplasia type Maroteaux, Epiphyseal chondrodysplasia, Miura, Short stature with nonspecific skeletal abnormalities AD/AR 25 66
NSD1 Sotos syndrome, Weaver syndrome, Beckwith-Wiedemann syndrome AD 268 509
NSDHL Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome), CK syndrome XL 15 28
OBSL1 3-M syndrome AR 12 29
ORC1 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 9 9
ORC4 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 22 5
ORC6 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 7 6
P3H1 Osteogenesis imperfecta AR 13 55
PAPSS2 Brachyolmia 4 with mild epiphyseal and metaphyseal changes, SEMD PAPPS2 type AR 10 19
PCNT Microcephalic osteodysplastic primordial dwarfism AR 42 83
PEX7 Refsum disease, Rhizomelic CDP type 1 AR 36 52
PHEX Hypophosphatemic rickets XL 254 426
PIK3CA* Cowden syndrome, CLOVES AD 83 46
PLOD2 Bruck syndrome, Osteogenesis imperfecta type 3 AR 8 13
POLR1C Treacher Collins syndrome AR 16 20
POR Disordered steroidogenesis due to cytochrome p450 oxidoreductase deficiency, Antley-Bixler syndrome AR 12 67
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 63 174
PTH1R Metaphyseal chondrodysplasia Jansen type, Failure of tooth eruption, Eiken dysplasia, Blomstrand dysplasia AD/AR 13 40
PTPN11 LEOPARD syndrome, Noonan syndrome, Metachondromatosis AD 124 135
PYCR1 Cutis laxa AR type 2B AR 14 36
RBPJ* Adams-Oliver syndrome AD 3 4
RECQL4 Baller-Gerold syndrome, RAPADILINO syndrome, Rothmund-Thomson syndrome AR 43 96
RMRP Cartilage-hair hypoplasia, Metaphyseal dysplasia without hypotrichosis, Anauxetic dysplasia AR 29 123
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 18 40
RUNX2 Cleidocranial dysplasia, Metaphyseal dysplasia with maxillary hypoplasia AD 22 210
SBDS* Aplastic anemia, Shwachman-Diamond syndrome, Severe spondylometaphyseal dysplasia AD/AR 18 88
SERPINF1 Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4 AR 8 35
SERPINH1 Osteogenesis imperfecta type 3 AR 3 3
SF3B4 Acrofacial dysostosis 1, Nager AD 26 36
SHOX* Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia, Short stature XL/PAR 24 424
SKI Shprintzen-Goldberg syndrome AD 16 20
SLC26A2 Diastrophic dysplasia, Atelosteogenesis type 2, De la Chapelle dysplasia, Recessive Multiple Epiphyseal dysplasia, Achondrogenesis type 1B AR 54 50
SLC29A3 Histiocytosis-lymphadenopathy plus syndrome, Dysosteosclerosis AR 16 23
SLC34A3 Hypophosphatemic rickets with hypercalciuria AR 21 36
SLC39A13 Spondylodysplastic Ehlers-Danlos syndrome AR 2 8
SLCO2A1 Hypertrophic osteoarthropathy AD/AR 13 51
SMAD3 Aneurysms-osteoarthritis syndrome, Loeys-Dietz syndrome AD 35 53
SMAD4 Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Polyposis, juvenile intestinal, Myhre dysplasia, Hereditary hemorrhagic telangiectasia AD 139 132
SMARCAL1 Schimke immunoosseous dysplasia AR 12 75
SMC1A Cornelia de Lange syndrome XL 50 84
SMC3 Cornelia de Lange syndrome AD 20 20
SOX9 Campomelic dysplasia, 46,XY sex reversal, Brachydactyly with anonychia (Cooks syndrome) AD 34 139
TBX3 Ulnar-Mammary syndrome AD 6 20
TCF12 Craniosynostosis AD 18 52
TCIRG1 Osteopetrosis, severe neonatal or infantile forms (OPTB1) AD/AR 12 124
TCOF1 Treacher Collins syndrome AD 31 320
TCTN3 Orofaciodigital syndrome (Mohr-Majewski syndrome), Joubert syndrome AR 9 10
TGFB1 Diaphyseal dysplasia Camurati-Engelmann AD 12 17
TGFB2 Loeys-Dietz syndrome AD 25 27
TGFB3 Loeys-Dietz syndrome (Reinhoff syndrome), Arrhythmogenic right ventricular dysplasia AD 13 19
TGFBR1 Loeys-Dietz syndrome AD 28 68
TGFBR2 Loeys-Dietz syndrome AD 57 132
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
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 52 114
TRAPPC2* Spondyloepiphyseal dysplasia tarda XL 12 54
TRPS1 Trichorhinophalangeal syndrome type 1, Trichorhinophalangeal syndrome type 3 AD 55 137
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 58 74
TTC21B Short-rib thoracic dysplasia, Nephronophthisis, Asphyxiating thoracic dysplasia (ATD; Jeune) AR 8 53
TWIST1 Saethre-Chotzen syndrome, Robinow-Sorauf syndrome, Craniosynostosis AD 16 190
TYROBP Nasu-Hakola disease, Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy AR 8 14
VDR Vitamin D-dependent rickets AD/AR 18 65
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 20 28
WDR34 Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune) AR 10 15
WDR35 Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2, Short rib-polydactyly syndrome type 5 AR 19 28
WISP3 Arthropathy, progressive pseudorheumatoid, of childhood, Spondyloepiphyseal dysplasia tarda with progressive arthropathy AR 13 69
WNT5A Robinow syndrome AD 5 6

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Gene Genomic location HG19 HGVS RefSeq RS-number
IFITM5 Chr11:299504 c.-14C>T NM_001025295.2 rs587776916 Explain almost all cases of OI type V PMID 23240094
SLC26A2 Chr5:149340544 c.-26+2T>C NM_000112.3 rs386833492

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist

 

This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.

 

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
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)

 

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

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

Blueprint Genetics offers a Comprehensive Skeletal Dysplasias and Disorders Panel that covers classical genes associated with skeletal dysplasia and disorders . The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint 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 statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. 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. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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Extra services

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ICD & CPT codes

CPT codes

SEQ 81479
DEL/DUP 81479


ICD codes

Commonly used ICD-10 codes when ordering the Comprehensive Skeletal Dysplasias and Disorders Panel

ICD-10 Disease
Q89.7 Skeletal dysplasia and disorders

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • 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.

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