Comprehensive Skeletal Dysplasias and Disorders Panel

SEQmethod-seq-icon Our Sequence Analysis is based on a proprietary targeted sequencing method OS-Seq™ and offers panels targeted for genes associated with certain phenotypes. A standard way to analyze NGS data for finding the genetic cause for Mendelian disorders. Results in 21 days. DEL/DUPmethod-dup-icon Targeted Del/Dup (CNV) analysis is used to detect bigger disease causing deletions or duplications from the disease-associated genes. Results in 21 days. PLUSmethod-plus-icon Plus Analysis combines Sequence + Del/Dup (CNV) Analysis providing increased diagnostic yield in certain clinical conditions, where the underlying genetic defect may be detectable by either of the analysis methods. Results in 21 days.

Test code: MA3301

The Blueprint Genetics Comprehensive Skeletal Dysplasias and Disorders Panel is a 186-gene test for genetic diagnostics of patients with clinical suspicion of skeletal dysplasia and disorders.

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.

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.

Genes in the Comprehensive Skeletal Dysplasias and Disorders Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
ACP5Spondyloenchondrodysplasia with immune dysregulationAR1024
ACVR1Fibrodysplasia ossificans progressivaAD1218
ADAMTS10Weill-Marchesani syndromeAR813
ADAMTSL2Geleophysic dysplasiaAR726
AGPSAR48
AKT1Proteus syndrome, Cowden syndromeAD39
ALPLOdontohypophosphatasiaAD/AR32270
ALX3AR77
ALX4AD/AR1322
AMER1Osteopathia striata with cranial sclerosisXL934
ANKHAD1221
ANO5Gnathodiaphyseal dysplasiaAR42106
ARHGAP31Adams-Oliver syndromeAD24
ARSE*XL1646
ATP6V0A2Cutis laxa, Wrinkly skin syndromeAR1652
B3GALT6Spondyloepimetaphyseal dysplasia with joint laxity, Ehlers-Danlos syndromeAR1422
B4GALT7Ehlers-Danlos syndrome, progeroid formAR88
BHLHA9AR429
BMP1Osteogenesis imperfectaAR611
BMP2AD126
BMPR1BAcromesomelic dysplasia, Demirhan, Brachydactyly C/Symphalangism-like phenoAD/AR1113
CA2Osteopetrosis, with renal tubular acidosisAR830
CANT1Desbuquois dysplasiaAR1725
CASRHypocalcemiaAD/AR78392
CDC6Meier-Gorlin syndrome (Ear-patella-short stature syndrome)AR13
CDKN1CBeckwith-Wiedemann syndrome, IMAGE syndromeAD2579
CDT1Meier-Gorlin syndrome (Ear-patella-short stature syndrome)AR68
CHST3Spondyloepiphyseal dysplasia with congenital joint dislocations (recessive Larsen syndrome)AR1335
CHST14Ehlers-Danlos syndrome, musculocontracturalAR1021
CLCN5Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis, Hypophosphatemic rickets,, Nephrolithiasis, I, Dent diseaseXL37255
CLCN7OsteopetrosisAD/AR991
COL1A1Ehlers-Danlos syndromeAD120883
COL1A2Ehlers-Danlos syndrome, cardiac valvular formAD79473
COL2A1Avascular necrosis of femoral head, Rhegmatogenous retinal detachment, Epiphyseal dysplasia, with myopia and deafness, Czech dysplasiaAD106537
COL9A1AR34
COL9A2Stickler syndromeAR512
COL9A3AD316
COL10A1Metaphyseal chondrodysplasia, SchmidAD2050
COL11A1Marshall syndrome, FibrochondrogenesisAD/AR1876
COL11A2Weissenbacher-Zweymuller syndrome, Deafness, Otospondylomegaepiphyseal dysplasia, FibrochondrogenesisAD/AR1751
COMPPseudoachondroplasia, Multiple ephiphyseal dysplasiaAD33182
CREBBPRubinstein-Taybi syndromeAD103332
CRTAPAR1124
CSPP1Jeune Asphyxiating Thoracic Dystrophy, Joubert syndromeAR2223
CTSKPycnodysostosisAR753
CUL73-M syndrome, Yakut short stature syndromeAR1868
CYP27B1Vitamin D-dependent ricketsAR2075
DHCR24DesmosterolosisAR68
DLL3Spondylocostal dysostosisAR921
DLL4Adams-Oliver syndromeAD910
DLX3Amelogenesis imperfecta, Trichodontoosseous syndromeAD26
DOCK6Adams-Oliver syndromeAR1319
DVL1Robinow syndromeAD913
DYMDyggve-Melchior-Clausen dysplasia, Smith-McCort dysplasiaAR2028
DYNC2H1AR/Digenic3498
EBPChondrodysplasia punctata, Male EBP disorder with neurologic defects (MEND)XL4389
EFNB1Craniofrontonasal dysplasiaXL15115
EFTUD2Mandibulofacial dysostosis with microcephaly, Esophageal atresia, syndromicAD1688
EIF2AK3AR771
ENAMAmelogenesis imperfectaAR318
ENPP1Arterial calcification, Hypophosphatemic ricketsAR1772
EOGTAdams-Oliver syndromeAR33
EP300Rubinstein-Taybi syndromeAD2143
ESCO2SC phocomelia syndrome, Roberts syndromeAR2930
EVCWeyers acrofacial dysostosis, Ellis-van Creveld syndromeAD/AR777
EVC2Ellis-van Creveld syndrome, Weyers acrodental dysostosisAD/AR2366
EXT1AD28479
EXT2AD20230
EZH2Weaver syndromeAD1436
FAM20AAmelogenesis imperfecta (Enamel-renal syndrome)AR940
FAM20CHypophosphatemia, hyperphosphaturia, dental anomalies, intracerebral calcifications and osteosclerosis (Raine syndrome)AR1322
FAM83HAmelogenesis imperfectaAD1327
FANCBFanconi anemiaXL714
FANCCFanconi anemiaAR3434
FBN1MASS syndrome, Shprintzen-Goldberg syndrome, Marfan syndromeAD5192056
FBN2Congenital contractural arachnodactyly (Beals syndrome)AD3085
FGF23Tumoral calcinosis, hyperphosphatemic, Hypophosphatemic ricketsAD/AR716
FGFR1Pfeiffer syndrome, Trigonocephaly, Hypogonadotropic hypogonadismAD/Digenic/Multigenic41232
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 syndromeAD47145
FGFR3Lacrimoauriculodentodigital syndrome, Muenke syndrome, Crouzon syndrome with acanthosis nigricans, Camptodactyly, tall stature, and hearing loss (CATSHL) syndromeAD/AR4768
FKBP10AR1727
FLNAXL86209
FLNBAD/AR3898
GDF5Multiple synostoses syndrome, Fibular hypoplasia and complex brachydactyly, Acromesomelic dysplasia, Hunter-Thompson, Symphalangism, proximal, ChondrodysplasiaAD/AR2252
GJA1*AD23103
GLI3Acrocallosal syndrome, Pallister-Hall syndrome, Grieg cephalopolysndactyly syndromeAD49221
GNASMcCune-Albright syndrome, Progressive osseous heteroplasia, PseudohypoparathyroidismAD45257
GNPATRhizomelic chondrodysplasia punctata, rhizomelicAR814
HDAC8Cornelia de Lange syndromeXL1840
HOXA13Hand-foot-uterus syndrome, Hand-foot-genital syndrome, Guttmacher syndromeAD822
HOXD13Brachydactyly-syndactyly syndrome, Synopolydactyly, Syndactyly, Synopolydactyly with cleftingAD/AR1838
HSPG2Schwartz-Jampel syndromeAD/AR1552
IFT80Short -rib thoracic dysplasia with or without polydactylyAR57
IFT122*Sensenbrenner syndromeAR913
IFT140Short -rib thoracic dysplasia with or without polydactylyAR1446
IFT172Retinitis pigmentosa, Short -rib thoracic dysplasia with or without polydactylyAR1821
IHHAcrocapitofemoral dysplasia, BrachydactylyAD/AR1117
IKBKG*Incontinentia pigmenti, Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency, Immunodeficiency, Invasive pneumococcal disease, recurrent, isolatedXL30141
KAT6BOhdo syndrome, SBBYS variant, Genitopatellar syndromeAD2353
KIF7Acrocallosal syndrome, Hydrolethalus syndrome, Al-Gazali-Bakalinova syndrome, Joubert syndromeAR/Digenic1339
LBRPelger-Huet anomaly, Reynolds syndrome, Greenberg/HEM skeletal dysplasia, Hydrops-ectopic calcification-moth-eaten skeletal dysplasiaAD1522
LEMD3Buschke-Ollendorff syndrome, OsteopoikilosisAD929
LIFRStuve-Wiedemann dysplasiaAR928
LMNAHeart-hand syndrome, Slovenian, Limb-girdle muscular dystrophy, Muscular dystrophy, congenital, LMNA-related, Lipodystrophy (Dunnigan), Emery-Dreiffus muscular dystrophy, Malouf syndrome, Dilated cardiomyopathy (DCM)AD/AR183458
LMX1BNail-patella syndromeAD18190
LRP4Cenani-Lenz syndactyly syndrome, Sclerosteosis, Myasthenic syndrome, congenitalAD/AR1223
LRP5*Van Buchem disease, Osteoporosis-pseudoglioma syndrome, Hyperostosis, endosteal, Osteosclerosis, Exudative vitreoretinopathyAD/AR/Digenic36163
LTBP2Weill-Marchesani syndrome, Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, Glaucoma, primary congenitalAR2123
MATN3AD/AR825
MMP9Metaphyseal anadysplasiaAR112
MSX2*Parietal foramina, Parietal foramina with cleidocranial dysplasiaAD924
NEK1Short -rib thoracic dysplasia with or without polydactylyAR/Digenic810
NF1*Watson syndrome, Neurofibromatosis, Neurofibromatosis-Noonan syndromeAD2612607
NFIXMarshall-SmithsyndromeAD2751
NIPBLCornelia de Lange syndromeAD246404
NOGTarsal-carpal coalition syndrome, Multiple synostosis syndrome, Stapes ankylosis with broad thumb and toes (Teunissen-Cremers syndrome), Symphalangism, proximalAD1861
NOTCH2*Alagille syndromeAD2156
NPR2Acromesomelic dysplasia type Maroteaux, Epiphyseal chondrodysplasia, Miura, Short stature with nonspecific skeletal abnormalitiesAD/AR1461
NSD1Sotos syndrome, Weaver syndrome, Beckwith-Wiedemann syndromeAD212461
NSDHLCongenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome), CK syndromeXL1528
OBSL13-M syndromeAR922
ORC1Meier-Gorlin syndrome (Ear-patella-short stature syndrome)AR99
ORC4Meier-Gorlin syndrome (Ear-patella-short stature syndrome)AR135
ORC6Meier-Gorlin syndrome (Ear-patella-short stature syndrome)AR55
P3H1Osteogenesis imperfectaAR1233
PAPSS2Brachyolmia 4 with mild epiphyseal and metaphyseal changesAR1021
PCNTMicrocephalic osteodysplastic primordial dwarfismAR3082
PEX7Refsum diseaseAR1751
PHEXHypophosphatemic ricketsXL75411
PIK3CA*Cowden syndromeAD3044
PLOD2Bruck syndromeAR411
POLR1CTreacher Collins syndromeAR1318
PORDisordered steroidogenesis due to cytochrome p450 oxidoreductase deficiencyAR1284
PPIBAR611
PRKAR1AMyxoma, intracardiac, Acrodysostosis, Pigmented nodular adrenocortical disease, Carney complexAD50173
PTH1RMetaphyseal chondrodysplasia Jansen type, Failure of tooth eruption, Eiken dysplasia, Blomstrand dysplasiaAD/AR1340
PTPN11LEOPARD syndrome, Noonan syndromeAD122129
PYCR1AR1234
RBPJ*Adams-Oliver syndromeAD23
RECQL4Baller-Gerold syndrome, RAPADILINO syndrome, Rothmund-Thomson syndromeAR3492
RMRPCartilage-hair hypoplasia, Metaphyseal dysplasia without hypotrichosis, Anauxetic dysplasiaAR24119
RNU4ATACRoifman syndromeAR1518
ROR2AD/AR1837
RUNX2Cleidocranial dysplasia, Metaphyseal dysplasia with maxillary hypoplasiaAD19203
SBDS*Aplastic anemia, Shwachman-Diamond syndromeAD/AR1288
SERPINF1AR729
SERPINH1AR35
SF3B4Acrofacial dysostosis 1, NagerAD2533
SHOX*Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia, Short statureXL/PAR23366
SKIShprintzen-Goldberg syndromeAD1520
SLC26A2Diastrophic dysplasia, Atelosteogenesis type 2, De la Chapelle dysplasiaAR3251
SLC29A3Histiocytosis-lymphadenopathy plus syndromeAR1722
SLC34A3Hypophosphatemic rickets with hypercalciuriaAR1036
SLC39A13Spondylodysplastic Ehlers-Danlos syndromeAR27
SLCO2A1Hypertrophic osteoarthropathyAD/AR946
SMAD3Aneurysms-osteoarthritis syndrome, Loeys-Dietz syndromeAD2650
SMAD4Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Polyposis, juvenile intestinal, Myhre dysplasia, Hereditary hemorrhagic telangiectasiaAD119128
SMARCAL1Schimke immunoosseous dysplasiaAR970
SMC1ACornelia de Lange syndromeXL3954
SMC3Cornelia de Lange syndromeAD1416
SOX9Campomelic dysplasia, 46,XY sex reversalAD24135
TBX3Ulnar-Mammary syndromeAD521
TCF12CraniosynostosisAD1352
TCIRG1AR9127
TCOF1Treacher Collins syndromeAD17303
TCTN3Orofaciodigital syndrome (Mohr-Majewski syndrome), Joubert syndromeAR810
TGFB1Diaphyseal dysplasia Camurati-EngelmannAD1128
TGFB2Loeys-Dietz syndromeAD1524
TGFB3Loeys-Dietz syndrome (Reinhoff syndrome), Arrhythmogenic right ventricular dysplasiaAD818
TGFBR1Loeys-Dietz syndromeAD2567
TGFBR2Loeys-Dietz syndromeAD54130
TNFRSF11AFamilial expansile osteolysis, Paget disease of boneAD/AR822
TNFRSF11BPaget disease of bone, juvenileAR821
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 syndromeAD38114
TRAPPC2*Spondyloepiphyseal dysplasia tardaXL1254
TRPS1AD18127
TRPV4Metatropic dysplasia, Spondyloepiphyseal dysplasia Maroteaux type, Parastremmatic dwarfism, Hereditary motor and sensory neuropathy, Spondylometaphyseal dysplasia Kozlowski type, Spinal muscular atrophy, Charcot-Marie-Tooth diseaseAD5371
TTC21BShort-rib thoracic dysplasia, NephronophthisisAR647
TWIST1Saethre-Chotzen syndrome, Robinow-Sorauf syndrome, CraniosynostosisAD14188
TYROBPNasu-Hakola disease, Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathyAR814
VDRVitamin D-dependent ricketsAD/AR1767
WDR19Retinitis pigmentosa, Nephronophthisis, Short -rib thoracic dysplasia with or without polydactyly, Senior-Loken syndromeAD/AR1625
WDR34Short -rib thoracic dysplasia with or without polydactylyAR1015
WDR35AR1524
WISP3Arthropathy, progressive pseudorheumatoid, of childhood, Spondyloepiphyseal dysplasia tarda with progressive arthropathyAR1368
WNT5ARobinow syndromeAD55
  • * 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.

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.

Please see our latest validation report showing sensitivity and specificity for SNPs and indels, sequencing depth, % of the nucleotides reached at least 15x coverage etc. If the Panel is not present in the report, data will be published when the Panel becomes available for ordering. 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. All the Panels available for ordering have sensitivity and specificity higher than > 0.99 to detect single nucleotide polymorphisms and a high sensitivity for indels ranging 1-19 bp. 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. Detection limit for Del/Dup analysis varies through the genome from one to six exon Del/Dups depending on exon size, sequencing coverage and sequence content.

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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ICD & CPT codes

CPT codes

SEQ81479
DEL/DUP81479


ICD codes

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

ICD-10Disease
Q87Skeletal 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.