Skeletal Dysplasias Core 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: MA3501

The Blueprint Genetics Skeletal Dysplasias Core Panel is a 107-gene test for genetic diagnostics of patients with clinical suspicion of skeletal dysplasia.

Inherited skeletal disorders are known to be sometimes difficult to differentiate from each other on clinical and radiological findings. This subpanel covers the major genes listed in the Nosology and Classification of Genetic Skeletal Disorders 2015 Revision (PMID: 26394607) for skeletal dysplasias. This panel covers 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 dysplasias and Ellis-van Creveld syndrome), various subtypes of osteogenesis imperfecta, campomelic dysplasia, slender bone dysplasias, multiple epiphydeal dysplasias, chondrodysplasia punctata group of disorders, osteopetrosis and related disorders, abnormal mineralization group of disorders (eg hypopohosphatasia), dysostoses with predominant vertebral involvement and disorders with patellar dysostoses. This panel is part of Comprehensive Skeletal / Malformation Syndrome Panel and Comprehensive Skeletal Dysplasias and Disorders 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 Skeletal Dysplasias Core

This core skeletal dysplasia panel is designed to detect mutations responsible for various skeletal dysplasias. Some of the resulting skeletal dysplasias are severe and potentially lethal (such as thanatophoric dysplasia, different types of achondrogenesis, osteogenesis imperfecta type II). Other non-lethal skeletal dysplasias result in disproportionate short stature with possible other clinical findings. Achondroplasia is the most common cause of disproportionate short stature worldwide. It is characterized by rhizomelic shortening of the limbs, exaggerated lumbar lordosis, brachydactyly, and macrocephaly with frontal bossing and midface hypoplasia. Type II collagen defects (mutations in COL2A1 genes) have been identified in a spectrum of disorders ranging from perinatally lethal conditions to those with only mild arthropathy. As many different skeletal dysplasias have quite similar clinical and radiological findings, multigene panel testing would allow efficient diagnostic testing. Identification of causative mutation(s) would establish the inheritance mode in the family and enable genetic counselling of the family. In addition, identifying the causative mutation(s) provides essential information for the doctor taking care of the patient. This panel provides good diffential diagnostic power for the major genes causing skeletal dysplasias.

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.

Genes in the Skeletal Dysplasias Core Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
ACP5Spondyloenchondrodysplasia with immune dysregulationAR1024
ADAMTS10Weill-Marchesani syndromeAR813
ADAMTSL2Geleophysic dysplasiaAR726
AGPSRhizomelic chondrodysplasia punctata type 3AR48
ALPLOdontohypophosphatasia, Hypophosphatasia perinatal lethal, infantile, juvenile and adult formsAD/AR32270
ANKHCalcium pyrophosphate deposition disease (familial chondrocalcinosis type 2), Craniometaphyseal dysplasia autosomal dominant typeAD1221
ARSE*Chondrodysplasia punctata X-linked recessive, brachytelephalangic type (CDPX1)XL1646
B3GALT6Spondyloepimetaphyseal dysplasia with joint laxity, Ehlers-Danlos syndromeAR1422
BMP1Osteogenesis imperfectaAR611
BMPR1BAcromesomelic dysplasia, Demirhan, Brachydactyly C/Symphalangism-like pheno, Brachydactyly type A2AD/AR1113
CA2Osteopetrosis, with renal tubular acidosisAR830
CANT1Desbuquois dysplasiaAR1725
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
CLCN7OsteopetrosisAD/AR991
COL1A1Ehlers-Danlos syndrome, Caffey disease, Osteogenesis imperfecta type 1, Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4AD120883
COL1A2Ehlers-Danlos syndrome, cardiac valvular form, Osteogenesis imperfecta type 1, Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4AD79473
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 1AD106537
COL9A1Stickler syndrome recessive type, Multiple epiphyseal dysplasia type 6 (EDM6)AR34
COL9A2Stickler syndrome, Multiple epiphyseal dysplasia type 2 (EDM2)AR512
COL9A3Multiple epihyseal dysplasia type 3 (EDM3)AD316
COL10A1Metaphyseal chondrodysplasia, SchmidAD2050
COL11A1Marshall syndrome, Fibrochondrogenesis, Stickler syndrome type 2AD/AR1876
COL11A2Weissenbacher-Zweymuller syndrome, Deafness, Otospondylomegaepiphyseal dysplasia, Fibrochondrogenesis, Stickler syndrome type 3 (non-ocular)AD/AR1751
COMPPseudoachondroplasia, Multiple ephiphyseal dysplasiaAD33182
CRTAPOsteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4AR1124
CSPP1Jeune Asphyxiating Thoracic Dystrophy, Joubert syndromeAR2223
CTSKPycnodysostosisAR753
CUL73-M syndrome, Yakut short stature syndromeAR1868
CYP27B1Vitamin D-dependent ricketsAR2075
DHCR24DesmosterolosisAR68
DLL3Spondylocostal dysostosisAR921
DVL1Robinow syndromeAD913
DYMDyggve-Melchior-Clausen dysplasia, Smith-McCort dysplasiaAR2028
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/Digenic3498
EBPChondrodysplasia punctata, Male EBP disorder with neurologic defects (MEND)XL4389
EIF2AK3SED, Wolcott-Rallison typeAR771
ENPP1Arterial calcification, Hypophosphatemic ricketsAR1772
ESCO2SC phocomelia syndrome, Roberts syndromeAR2930
EVCWeyers acrofacial dysostosis, Ellis-van Creveld syndromeAD/AR777
EVC2Ellis-van Creveld syndrome, Weyers acrodental dysostosisAD/AR2366
FAM20CHypophosphatemia, hyperphosphaturia, dental anomalies, intracerebral calcifications and osteosclerosis (Raine syndrome)AR1322
FGF23Tumoral calcinosis, hyperphosphatemic, Hypophosphatemic ricketsAD/AR716
FGFR1Pfeiffer syndrome, Trigonocephaly, Hypogonadotropic hypogonadism, Osteoglophonic Dwarfism - Craniostenosis, Hartsfield syndromeAD/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 syndrome, Bent bone dysplasiaAD47145
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/AR4768
FKBP10Bruck syndrome type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4AR1727
FLNAFrontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defectsXL86209
FLNBLarsen syndrome (dominant), Atelosteogenesis type 1, Atelosteogenesis type 3, Spondylo-carpal-tarsal dyspasiaAD/AR3898
GDF5Multiple synostoses syndrome, Fibular hypoplasia and complex brachydactyly, Acromesomelic dysplasia, Hunter-Thompson, Symphalangism, proximal, Chondrodysplasia, Brachydactyly type A2, Brachydactyly type C, Grebe dysplasiaAD/AR2252
GNPATRhizomelic chondrodysplasia punctata, rhizomelicAR814
HSPG2Schwartz-Jampel syndrome, Dyssegmental dysplasia Silverman-Handmaker type, Dyssegmental dysplasia Rolland-Desbuquis typeAD/AR1552
IFT80Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune)AR57
IFT140Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune)AR1446
IFT172Retinitis pigmentosa, Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune)AR1821
IHHAcrocapitofemoral dysplasia, Brachydactyly, Syndactyly type LuekenAD/AR1117
IKBKG*Incontinentia pigmenti, Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency, Immunodeficiency, Invasive pneumococcal disease, recurrent, isolated, Osteopetrosis with ectodermal dysplasia and immune defect (OLEDAID)XL30141
KAT6BOhdo syndrome, SBBYS variant, Genitopatellar syndromeAD2353
LBRPelger-Huet anomaly, Reynolds syndrome, Greenberg/HEM skeletal dysplasia, Hydrops-ectopic calcification-moth-eaten skeletal dysplasiaAD1522
LIFRStuve-Wiedemann dysplasia, Schwartz-Jampel type 2 syndromeAR928
LMX1BNail-patella syndromeAD18190
LRP5*Van Buchem disease, Osteoporosis-pseudoglioma syndrome, Hyperostosis, endosteal, Osteosclerosis, Exudative vitreoretinopathy, Osteopetrosis late-onset form type 1, LRP5 primary osteoporosisAD/AR/Digenic36163
LTBP2Weill-Marchesani syndrome, Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, Glaucoma, primary congenitalAR2123
MATN3Spondyloepimetaphyseal dysplasia Matrilin type, Multiple epiphyseal dysplasia type 5 (EDM5)AD/AR825
MMP9Metaphyseal anadysplasiaAR112
NEK1Short -rib thoracic dysplasia with or without polydactyly, SRPS type 2 (Majewski)AR/Digenic810
NPR2Acromesomelic dysplasia type Maroteaux, Epiphyseal chondrodysplasia, Miura, Short stature with nonspecific skeletal abnormalitiesAD/AR1461
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 changes, SEMD PAPPS2 typeAR1021
PCNTMicrocephalic osteodysplastic primordial dwarfismAR3082
PEX7Refsum disease, Rhizomelic CDP type 1AR1751
PHEXHypophosphatemic ricketsXL75411
PLOD2Bruck syndrome, Osteogenesis imperfecta type 3AR411
PPIBOsteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4AR611
PTH1RMetaphyseal chondrodysplasia Jansen type, Failure of tooth eruption, Eiken dysplasia, Blomstrand dysplasiaAD/AR1340
RMRPCartilage-hair hypoplasia, Metaphyseal dysplasia without hypotrichosis, Anauxetic dysplasiaAR24119
RNU4ATACRoifman syndrome, Microcephalic osteodysplastic primordial dwarfism type 1, Microcephalic osteodysplastic primordial dwarfism type 3AR1518
ROR2Robinow syndrome recessive type, Brachydactyly type BAD/AR1837
RUNX2Cleidocranial dysplasia, Metaphyseal dysplasia with maxillary hypoplasiaAD19203
SBDS*Aplastic anemia, Shwachman-Diamond syndrome, Severe spondylometaphyseal dysplasiaAD/AR1288
SERPINF1Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4AR729
SERPINH1Osteogenesis imperfecta type 3AR35
SHOX*Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia, Short statureXL/PAR23366
SLC26A2Diastrophic dysplasia, Atelosteogenesis type 2, De la Chapelle dysplasia, Recessive Multiple Epiphyseal dysplasia, Achondrogenesis type 1BAR3251
SLC34A3Hypophosphatemic rickets with hypercalciuriaAR1036
SLC39A13Spondylodysplastic Ehlers-Danlos syndromeAR27
SMAD4Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Polyposis, juvenile intestinal, Myhre dysplasia, Hereditary hemorrhagic telangiectasiaAD119128
SMARCAL1Schimke immunoosseous dysplasiaAR970
SOX9Campomelic dysplasia, 46,XY sex reversal, Brachydactyly with anonychia (Cooks syndrome)AD24135
TCIRG1Osteopetrosis, severe neonatal or infantile forms (OPTB1)AR9127
TGFB1Diaphyseal dysplasia Camurati-EngelmannAD1128
TNFRSF11AFamilial expansile osteolysis, Paget disease of bone, Osteopetrosis, severe neonatal or infantile forms (OPTB1)AD/AR822
TNFRSF11BPaget disease of bone, juvenileAR821
TRAPPC2*Spondyloepiphyseal dysplasia tardaXL1254
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 brachydactylyAD5371
TTC21BShort-rib thoracic dysplasia, Nephronophthisis, Asphyxiating thoracic dysplasia (ATD; Jeune)AR647
VDRVitamin D-dependent ricketsAD/AR1767
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/AR1625
WDR35Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2, Short rib-polydactyly syndrome type 5AR1524
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 core panel that covers classical genes associated with skeletal dysplasia. 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

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.