- Is a 27 gene panel that includes assessment of non-coding variants
Is ideal for patients with a clinical suspicion of osteogenesis imperfecta. The genes on this panel are included in the Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel.
Number of genes27
CPT codesSEQ 81404
The Blueprint Genetics Osteogenesis Imperfecta Panel (test code MA3001):
- Is a 27 gene panel that includes assessment of selected non-coding disease-causing variants
- Is available as PLUS analysis (sequencing analysis and deletion/duplication analysis), sequencing analysis only or deletion/duplication analysis only
Commonly used ICD-10 code(s) when ordering the Osteogenesis Imperfecta Panel
- EDTA blood, min. 1 ml
- Purified DNA, min. 3μg
- Saliva (Oragene DNA OG-500 kit)
Label the sample tube with your patient’s name, date of birth and the date of sample collection.
Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.
Osteogenesis imperfecta (OI) phenotype is variable, ranging from osteoporosis presenting in adulthood to lethality in infancy. The two mildest forms, classic non-deforming OI and common variable OI, account for considerably more than half of all OI. About 90% of patients have mutations in type I collagen genes (COL1A1 and COL1A2). COL1A1/2-related OI is inherited in an autosomal dominant manner. Several additional genes have recently been identified. The primary differential diagnosis for individuals with features of COL1A1/2-related OI are autosomal recessive subtypes of OI. The proportion of cases caused by a de novo COL1A1 or COL1A2 mutation varies by the severity of disease: approximately 60% of cases of classic non-deforming OI with blue sclerae or common variable OI with normal sclerae, virtually 100% of perinatally lethal OI, and close to 100% of progressively deforming OI are de novo. Gonadal mosaicism may be present in 3%-5% of cases. Disease prevalence is approximately 6-7:100,000. The major clinical manifestation is skeletal fragility. Skeletal deformity, short stature, scoliosis and wormian bones may be present. Other extraskeletal manifestations may include hearing loss, dentinogenesis imperfecta, blue/gray sclerae, hypercalciuria, easy bruisability, increased laxity of the ligaments and skin and cardiovascular abnormalities. The differential diagnosis includes child abuse, rickets, osteomalacia, and other rare skeletal syndromes. We have included genes for hypophosphatasia on this panel for differential diagnostic purposes. We have also included genes for some syndromes/disorders where osteopenia/fractures is one of the findings for differential diagnostic purposes for cases with limited clinical information, such as newborns.
Genes in the Osteogenesis Imperfecta Panel and their clinical significance
|ALPL||Odontohypophosphatasia, Hypophosphatasia perinatal lethal, infantile, juvenile and adult forms||AD/AR||61||290|
|B3GAT3*||Multiple joint dislocations, short stature, craniofacial dysmorphism, and congenital heart defects||AR||5||13|
|B4GALT7||Ehlers-Danlos syndrome, progeroid form||AR||9||9|
|CLCN5||Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis, Hypophosphatemic rickets,, Nephrolithiasis, I, Dent disease||XL||45||267|
|COL1A1||Ehlers-Danlos syndrome, Caffey disease, Osteogenesis imperfecta type 1, Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4||AD||290||943|
|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||162||496|
|CREB3L1||Osteogenesis imperfecta, type XVI||AR||1|
|CRTAP||Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4||AR||12||28|
|FGF23||Tumoral calcinosis, hyperphosphatemic, Hypophosphatemic rickets||AD/AR||10||16|
|FKBP10||Bruck syndrome type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4||AR||20||37|
|IFITM5||Osteogenesis imperfecta type 5||AD||2||2|
|LRP5*||Van Buchem disease, Osteoporosis-pseudoglioma syndrome, Hyperostosis, endosteal, Osteosclerosis, Exudative vitreoretinopathy, Osteopetrosis late-onset form type 1, LRP5 primary osteoporosis||AD/AR/Digenic||55||188|
|MBTPS2||Keratosis follicularis spinulosa decalvans, IFAP syndrome, Palmoplantar keratoderma, mutilating, with periorificial keratotic plaques||XL||10||24|
|PLOD2||Bruck syndrome, Osteogenesis imperfecta type 3||AR||8||17|
|PLS3||Osteoporosis and osteoporotic fractures||XL||1||14|
|PPIB||Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4||AR||8||13|
|SEC24D||Cole-Carpenter syndrome 2||AR||4||11|
|SERPINF1||Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4||AR||9||35|
|SERPINH1||Osteogenesis imperfecta type 3||AR||3||3|
|SLC34A3||Hypophosphatemic rickets with hypercalciuria||AR||22||36|
|SP7||Osteogenesis imperfecta, type XII||AR||1||1|
|SPARC||Keratoconus, Osteogenesis imperfecta, type XVII||AD/AR||2||3|
|TMEM38B||Osteogenesis imperfecta, type XIV||AR||2||6|
|WNT1||Osteoprosis, autosomal dominant, Osteogenesis imperfecta, type XV||AD/AR||8||27|
* Some, or all, of the gene is duplicated in the genome. Read more.
# The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads).
The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#)
Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Orphanet databases.
Non-coding variants covered by the panel
|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|
Added and removed genes from the panel
|Genes added||Genes removed|
|B3GAT3 CREB3L1 IFITM5 MBTPS2 PLS3 SEC24D SP7 SPARC TMEM38B WNT1||ACTA1 ANO5 ATP6V0A2 B3GALNT2 CAPN3 CFL2 CHKB COL6A1 COL6A2 COL6A3 DNM2 EMD ENPP1 FHL1 FKRP FKTN FLNA FLNB GAA GMPPB ISPD KBTBD13 KLHL40 LAMA2 LAMP2 LARGE LMNA MYH7 NEB OCRL PIEZO2 POMGNT1 POMT1 POMT2 PYCR1 RAPSN RYR1 SELENON SIL1 TMEM43 TMEM5 TNNT1 TPM2 TPM3|
Test strengthThe strengths of this test include:
- CAP and ISO-15189 accreditations covering all operations at Blueprint Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
- CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
- Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
- Careful construction of clinically effective and scientifically justified gene panels
- Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
- Our publically available analytic validation demonstrating complete details of test performance
- ~1,500 non-coding disease causing variants in Blueprint WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
- Our rigorous variant classification based on modified ACMG variant classification scheme
- Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
- Our comprehensive clinical statements
Genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk (*) if they overlap with the UCSC pseudogene regions. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).This test does not detect the following:
- Complex inversions
- Gene conversions
- Balanced translocations
- Mitochondrial DNA variants
- Repeat expansion disorders unless specifically mentioned
- Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).
This test may not reliably detect the following:
- Low level mosaicism
- Stretches of mononucleotide repeats
- Indels larger than 50bp
- Single exon deletions or duplications
- Variants within pseudogene regions/duplicated segments
The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.
For additional information, please refer to the Test performance section and see our Analytic Validation.
The Blueprint Genetics osteogenesis imperfecta panel covers classical genes associated with osteogenesis imperfecta. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.
Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).
Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. Blueprint Genetics' Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient's phenotype is suggestive of a specific mutation type.
Performance of Blueprint Genetics Whole Exome Sequencing (WES) assay. All individual panels are sliced from WES data.
|Sensitivity % (TP/(TP+FN)||Specificity %|
|Single nucleotide variants||99.65% (412,456/413,893)||>99.99%|
|Insertions, deletions and indels by sequence analysis|
|1-10 bps||96.94% (17,070/17,608)||>99.99%|
|11-50 bps||99.07% (957/966)||>99.99%|
|Copy number variants (exon level dels/dups)|
|Clinical samples (small CNVs, n=52)|
|1 exon level deletion||92.3% (24/26)||NA|
|2 exons level deletion/duplication||100.0% (11/11)||NA|
|3-7 exons level deletion/duplication||93.3% (14/15)||NA|
|Microdeletion/-duplication sdrs (large CNVs, n=37))|
|Size range (0.1-47 Mb)||100% (37/37)|
|Simulated CNV detection|
|2 exons level deletion/duplication||90.98% (7,357/8,086)||99.96%|
|5 exons level deletion/duplication||98.63% (7,975/8,086)||99.98%|
|The performance presented above reached by WES with the following coverage metrics|
|Mean sequencing depth at exome level||174x|
|Nucleotides with >20x sequencing coverage (%)||99.4%|
The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. 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. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.
We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.
Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analyzed at our laboratory allowed us to further develop the industry standard.
The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant at least three times at Blueprint Genetics. Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at Blueprint Genetics.
Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, congress abstracts and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.
Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling. For eligible cases, Blueprint Genetics offers a no charge service to investigate the role of reported VUS (VUS Clarification Service).
Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.