Osteopetrosis and Dense Bone Dysplasia 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: MA2001

The Blueprint Genetics Osteopetrosis and Dense Bone Dysplasia Panel is a 21 gene test for genetic diagnostics of patients with clinical suspicion of osteopetrosis.

The osteopetroses are genetic diseases characterized by increased bone mass and density due to a failure in bone resorption. Osteopetrosis includes an autosomal dominant, autosomal recessive and X-linked form. The most severe form is fatal in infancy, has an autosomal recessive inheritance and can often be cured with hematopoietic stem cell transplantation. The differential diagnoses include other disorders, which can cause diffuse osteosclerosis, such as hypervitaminosis D and hypoparathyroidism and Paget's disease. This panel is designed in order to improve diagnosis rate, turn-around time and costs in patients with suspected osteopetrosis. This panel is part of the Comprehensive Skeletal / Malformation Syndrome panel.

About Osteopetrosis and Dense Bone Dysplasia

Autosomal dominant osteopetrosis (ADO, alsoknown as Albers-Schönberg disease) is usually considered an adult-onset, more benign form whereas autosomal recessive osteopetrosis (ARO), also termed malignant infantile osteopetrosis, presents soon after birth, is often severe and leads to death if left untreated. Osteopetrosis caused by hypomorphic mutations in the IKBKG gene is X-chromosomal form of the disease. Autosomal recessive osteopetrosis (ARO) is a genetically and phenotypically heterogeneous disease; most forms result from late endosomal trafficking defects that prevent osteoclast ruffled‐border formation. Haematopoietic stem cell transplantation (HSCT) can cure ARO if given in early life to patients with osteoclast‐intrinsic disease without neurodegenerative complications (PubMed: 23877423). New treatments that target RANKL/RANK signalling offer promise in ARO subtypes that currently cannot be cured by HSCT and to prevent hypercalcaemia after HSCT.

Paget's disease is a common metabolic bone disease characterized by focal abnormalities of increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Bone lesions in this disorder show evidence of increased osteoclastic bone resorption and disorganized bone structure. Genetic factors play an important role in the disease (PubMed: 24988994). In some cases, Paget's disease is inherited in an autosomal dominant manner and the most common cause for this is a mutation in the SQSTM1 gene. Mutations in TNFRSF11A, TNFRSF11B and VCP have been identified in rare syndromes with Padget's disease-like features.

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 Osteopetrosis and Dense Bone Dysplasia Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
AMER1Osteopathia striata with cranial sclerosisXL934
ANKHCalcium pyrophosphate deposition disease (familial chondrocalcinosis type 2), Craniometaphyseal dysplasia autosomal dominant typeAD1221
CA2Osteopetrosis, with renal tubular acidosisAR830
CLCN7OsteopetrosisAD/AR991
COL1A1Ehlers-Danlos syndrome, Caffey disease, Osteogenesis imperfecta type 1, Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4AD120883
CTSKPycnodysostosisAR753
DLX3Amelogenesis imperfecta, Trichodontoosseous syndromeAD26
FAM20CHypophosphatemia, hyperphosphaturia, dental anomalies, intracerebral calcifications and osteosclerosis (Raine syndrome)AR1322
GJA1*Oculodentodigital dysplasia mild type, Oculodentodigital dysplasia severe type, Syndactyly type 3AD23103
IKBKG*Incontinentia pigmenti, Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency, Immunodeficiency, Invasive pneumococcal disease, recurrent, isolated, Osteopetrosis with ectodermal dysplasia and immune defect (OLEDAID)XL30141
LEMD3Buschke-Ollendorff syndrome, OsteopoikilosisAD929
LRP4Cenani-Lenz syndactyly syndrome, Sclerosteosis, Myasthenic syndrome, congenitalAD/AR1223
LRP5*Van Buchem disease, Osteoporosis-pseudoglioma syndrome, Hyperostosis, endosteal, Osteosclerosis, Exudative vitreoretinopathy, Osteopetrosis late-onset form type 1, LRP5 primary osteoporosisAD/AR/Digenic36163
PTH1RMetaphyseal chondrodysplasia Jansen type, Failure of tooth eruption, Eiken dysplasia, Blomstrand dysplasiaAD/AR1340
SLC29A3Histiocytosis-lymphadenopathy plus syndrome, DysosteosclerosisAR1722
SLCO2A1Hypertrophic osteoarthropathyAD/AR946
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
TYROBPNasu-Hakola disease, Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathyAR814
  • * 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 osteopetrosis and dense bone dysplasia panel that covers classical genes associated with osteopetrosis. 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 Osteopetrosis and Dense Bone Dysplasia Panel

ICD-10Disease
Q78.2Osteopetrosis

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.