Skeletal Dysplasias Core Panel
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.
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.
|ACP5||Spondyloenchondrodysplasia with immune dysregulation||AR||10||24|
|AGPS||Rhizomelic chondrodysplasia punctata type 3||AR||4||8|
|ALPL||Odontohypophosphatasia, Hypophosphatasia perinatal lethal, infantile, juvenile and adult forms||AD/AR||32||270|
|ANKH||Calcium pyrophosphate deposition disease (familial chondrocalcinosis type 2), Craniometaphyseal dysplasia autosomal dominant type||AD||12||21|
|ARSE*||Chondrodysplasia punctata X-linked recessive, brachytelephalangic type (CDPX1)||XL||16||46|
|B3GALT6||Spondyloepimetaphyseal dysplasia with joint laxity, Ehlers-Danlos syndrome||AR||14||22|
|BMPR1B||Acromesomelic dysplasia, Demirhan, Brachydactyly C/Symphalangism-like pheno, Brachydactyly type A2||AD/AR||11||13|
|CA2||Osteopetrosis, with renal tubular acidosis||AR||8||30|
|CDC6||Meier-Gorlin syndrome (Ear-patella-short stature syndrome)||AR||1||3|
|CDKN1C||Beckwith-Wiedemann syndrome, IMAGE syndrome||AD||25||79|
|CDT1||Meier-Gorlin syndrome (Ear-patella-short stature syndrome)||AR||6||8|
|CHST3||Spondyloepiphyseal dysplasia with congenital joint dislocations (recessive Larsen syndrome)||AR||13||35|
|COL1A1||Ehlers-Danlos syndrome, Caffey disease, Osteogenesis imperfecta type 1, Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4||AD||120||883|
|COL1A2||Ehlers-Danlos syndrome, cardiac valvular form, Osteogenesis imperfecta type 1, Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4||AD||79||473|
|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||106||537|
|COL9A1||Stickler syndrome recessive type, Multiple epiphyseal dysplasia type 6 (EDM6)||AR||3||4|
|COL9A2||Stickler syndrome, Multiple epiphyseal dysplasia type 2 (EDM2)||AR||5||12|
|COL9A3||Multiple epihyseal dysplasia type 3 (EDM3)||AD||3||16|
|COL10A1||Metaphyseal chondrodysplasia, Schmid||AD||20||50|
|COL11A1||Marshall syndrome, Fibrochondrogenesis, Stickler syndrome type 2||AD/AR||18||76|
|COL11A2||Weissenbacher-Zweymuller syndrome, Deafness, Otospondylomegaepiphyseal dysplasia, Fibrochondrogenesis, Stickler syndrome type 3 (non-ocular)||AD/AR||17||51|
|COMP||Pseudoachondroplasia, Multiple ephiphyseal dysplasia||AD||33||182|
|CRTAP||Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4||AR||11||24|
|CSPP1||Jeune Asphyxiating Thoracic Dystrophy, Joubert syndrome||AR||22||23|
|CUL7||3-M syndrome, Yakut short stature syndrome||AR||18||68|
|CYP27B1||Vitamin D-dependent rickets||AR||20||75|
|DYM||Dyggve-Melchior-Clausen dysplasia, Smith-McCort dysplasia||AR||20||28|
|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||34||98|
|EBP||Chondrodysplasia punctata, Male EBP disorder with neurologic defects (MEND)||XL||43||89|
|EIF2AK3||SED, Wolcott-Rallison type||AR||7||71|
|ENPP1||Arterial calcification, Hypophosphatemic rickets||AR||17||72|
|ESCO2||SC phocomelia syndrome, Roberts syndrome||AR||29||30|
|EVC||Weyers acrofacial dysostosis, Ellis-van Creveld syndrome||AD/AR||7||77|
|EVC2||Ellis-van Creveld syndrome, Weyers acrodental dysostosis||AD/AR||23||66|
|FAM20C||Hypophosphatemia, hyperphosphaturia, dental anomalies, intracerebral calcifications and osteosclerosis (Raine syndrome)||AR||13||22|
|FGF23||Tumoral calcinosis, hyperphosphatemic, Hypophosphatemic rickets||AD/AR||7||16|
|FGFR1||Pfeiffer syndrome, Trigonocephaly, Hypogonadotropic hypogonadism, Osteoglophonic Dwarfism - Craniostenosis, Hartsfield syndrome||AD/Digenic/Multigenic||41||232|
|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||47||145|
|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||47||68|
|FKBP10||Bruck syndrome type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4||AR||17||27|
|FLNA||Frontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defects||XL||86||209|
|FLNB||Larsen syndrome (dominant), Atelosteogenesis type 1, Atelosteogenesis type 3, Spondylo-carpal-tarsal dyspasia||AD/AR||38||98|
|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||52|
|GNPAT||Rhizomelic chondrodysplasia punctata, rhizomelic||AR||8||14|
|HSPG2||Schwartz-Jampel syndrome, Dyssegmental dysplasia Silverman-Handmaker type, Dyssegmental dysplasia Rolland-Desbuquis type||AD/AR||15||52|
|IFT80||Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune)||AR||5||7|
|IFT140||Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune)||AR||14||46|
|IFT172||Retinitis pigmentosa, Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune)||AR||18||21|
|IHH||Acrocapitofemoral dysplasia, Brachydactyly, Syndactyly type Lueken||AD/AR||11||17|
|IKBKG*||Incontinentia pigmenti, Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency, Immunodeficiency, Invasive pneumococcal disease, recurrent, isolated, Osteopetrosis with ectodermal dysplasia and immune defect (OLEDAID)||XL||30||141|
|KAT6B||Ohdo syndrome, SBBYS variant, Genitopatellar syndrome||AD||23||53|
|LBR||Pelger-Huet anomaly, Reynolds syndrome, Greenberg/HEM skeletal dysplasia, Hydrops-ectopic calcification-moth-eaten skeletal dysplasia||AD||15||22|
|LIFR||Stuve-Wiedemann dysplasia, Schwartz-Jampel type 2 syndrome||AR||9||28|
|LRP5*||Van Buchem disease, Osteoporosis-pseudoglioma syndrome, Hyperostosis, endosteal, Osteosclerosis, Exudative vitreoretinopathy, Osteopetrosis late-onset form type 1, LRP5 primary osteoporosis||AD/AR/Digenic||36||163|
|LTBP2||Weill-Marchesani syndrome, Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, Glaucoma, primary congenital||AR||21||23|
|MATN3||Spondyloepimetaphyseal dysplasia Matrilin type, Multiple epiphyseal dysplasia type 5 (EDM5)||AD/AR||8||25|
|NEK1||Short -rib thoracic dysplasia with or without polydactyly, SRPS type 2 (Majewski)||AR/Digenic||8||10|
|NPR2||Acromesomelic dysplasia type Maroteaux, Epiphyseal chondrodysplasia, Miura, Short stature with nonspecific skeletal abnormalities||AD/AR||14||61|
|ORC1||Meier-Gorlin syndrome (Ear-patella-short stature syndrome)||AR||9||9|
|ORC4||Meier-Gorlin syndrome (Ear-patella-short stature syndrome)||AR||13||5|
|ORC6||Meier-Gorlin syndrome (Ear-patella-short stature syndrome)||AR||5||5|
|PAPSS2||Brachyolmia 4 with mild epiphyseal and metaphyseal changes, SEMD PAPPS2 type||AR||10||21|
|PCNT||Microcephalic osteodysplastic primordial dwarfism||AR||30||82|
|PEX7||Refsum disease, Rhizomelic CDP type 1||AR||17||51|
|PLOD2||Bruck syndrome, Osteogenesis imperfecta type 3||AR||4||11|
|PPIB||Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4||AR||6||11|
|PTH1R||Metaphyseal chondrodysplasia Jansen type, Failure of tooth eruption, Eiken dysplasia, Blomstrand dysplasia||AD/AR||13||40|
|RMRP||Cartilage-hair hypoplasia, Metaphyseal dysplasia without hypotrichosis, Anauxetic dysplasia||AR||24||119|
|RNU4ATAC||Roifman syndrome, Microcephalic osteodysplastic primordial dwarfism type 1, Microcephalic osteodysplastic primordial dwarfism type 3||AR||15||18|
|ROR2||Robinow syndrome recessive type, Brachydactyly type B||AD/AR||18||37|
|RUNX2||Cleidocranial dysplasia, Metaphyseal dysplasia with maxillary hypoplasia||AD||19||203|
|SBDS*||Aplastic anemia, Shwachman-Diamond syndrome, Severe spondylometaphyseal dysplasia||AD/AR||12||88|
|SERPINF1||Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4||AR||7||29|
|SERPINH1||Osteogenesis imperfecta type 3||AR||3||5|
|SHOX*||Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia, Short stature||XL/PAR||23||366|
|SLC26A2||Diastrophic dysplasia, Atelosteogenesis type 2, De la Chapelle dysplasia, Recessive Multiple Epiphyseal dysplasia, Achondrogenesis type 1B||AR||32||51|
|SLC34A3||Hypophosphatemic rickets with hypercalciuria||AR||10||36|
|SLC39A13||Spondylodysplastic Ehlers-Danlos syndrome||AR||2||7|
|SMAD4||Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Polyposis, juvenile intestinal, Myhre dysplasia, Hereditary hemorrhagic telangiectasia||AD||119||128|
|SMARCAL1||Schimke immunoosseous dysplasia||AR||9||70|
|SOX9||Campomelic dysplasia, 46,XY sex reversal, Brachydactyly with anonychia (Cooks syndrome)||AD||24||135|
|TCIRG1||Osteopetrosis, severe neonatal or infantile forms (OPTB1)||AR||9||127|
|TGFB1||Diaphyseal dysplasia Camurati-Engelmann||AD||11||28|
|TNFRSF11A||Familial expansile osteolysis, Paget disease of bone, Osteopetrosis, severe neonatal or infantile forms (OPTB1)||AD/AR||8||22|
|TNFRSF11B||Paget disease of bone, juvenile||AR||8||21|
|TRAPPC2*||Spondyloepiphyseal dysplasia tarda||XL||12||54|
|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||53||71|
|TTC21B||Short-rib thoracic dysplasia, Nephronophthisis, Asphyxiating thoracic dysplasia (ATD; Jeune)||AR||6||47|
|VDR||Vitamin D-dependent rickets||AD/AR||17||67|
|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||16||25|
|WDR35||Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2, Short rib-polydactyly syndrome type 5||AR||15||24|
|WISP3||Arthropathy, progressive pseudorheumatoid, of childhood, Spondyloepiphyseal dysplasia tarda with progressive arthropathy||AR||13||68|
- * 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||Comment||Reference|
|IFITM5||Chr11:299504||c.-14C>T||NM_001025295.2||rs587776916||Explain almost all cases of OI type V||PMID 23240094|
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.
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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Choose an analysis method
ICD & CPT codes
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.