Skeletal Dysplasia with Abnormal Mineralization 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: MA1301

The Blueprint Genetics Skeletal Dysplasia with Abnormal Mineralization Panel is a 27 gene test for genetic diagnostics of patients with clinical suspicion of hypophosphatasia or hypophosphatemic rickets.

Hypophosphatasia is a skeletal dysplasia with an extremely high clinical heterogeneity ranging from a perinatal lethal form to odontohypophosphatasia affecting only teeth. Osteogenesis imperfecta (OI) and campomelic dysplasia are the main differential diagnoses of severe hypophosphatasia. Hypophosphatemic rickets (HR) is also a heterogeneous disease of abnormal bone mineralization. Identification of the precise genetic defect is important to permit appropriate genetic counseling, anticipatory guidance, and early prenatal diagnosis. In HR, there is effective treatment that must be implemented from the time of diagnosis until growth is complete. This panel is designed to improve diagnosis rate, turn-around time and costs in patients with suspected defect in bone mineralization. This panel is part of the Comprehensive Skeletal / Malformation Syndrome panel. Blueprint Genetics offers also Osteogenesis Imperfecta Panel.

About Skeletal Dysplasia with Abnormal Mineralization

Hypophosphatasia is a rare inherited skeletal dysplasia due to loss of function mutations in the ALPL gene. It is characterized by defective mineralization of bone and/or teeth in the presence of low activity of serum and bone alkaline phosphatase. Clinical features range from stillbirth without mineralized bone at the severe end to pathologic fractures of the lower extremities in later adulthood at the mild end. At least six clinical forms are currently recognized based on age at diagnosis and severity of features. The differential diagnosis of hypophosphatasia depends on the age at which the diagnosis is considered. In utero, osteogenesis imperfecta (OI) type II and campomelic dysplasia are the most common differential diagnoses of. Rare conditions such as Stuve–Wiedemann syndrome may also be involved. At birth OI type II, campomelic dysplasia, and chondrodysplasias with bone mineralization defect are similar diseases and challenging even to radiographs. In infancy and childhood, different OI types are the most common differential diagnosis, but also more rare disorders such as cleidocranial dysostosis, Cole-Carpenter syndrome, idiopathic juvenile osteoporosis, and renal osteodystrophy should be considered. In adult osteopenia/osteoporosis and more rarely osteoarthritis and pseudogout may be caused by hypophosphatasia. Serum alkaline phosphatase activity can suggest the diagnosis pending confirmation with genetic testing. Resent results indicate that hypophosphatasia and OI may be easily misdiagnosed in the prenatal stage but also in adults with mild symptoms for these diseases (PubMed: 26432670).

Hypophosphatemic rickets (HR) is a genetic disorder, which prevents sufficient reabsorption of phosphate in the proximal renal tubule, with increased phosphate excretion, resulting in rickets. Rickets is a metabolic disorder of the growing bone, which occurs in children before fusion of the epiphysis and is characterized by impaired mineralization of the osteoid matrix during growth. Most common form of HR is inherited in an X-linked manner, but the remaining 20% of familial HR patients belong to the autosomal dominant HR and to the hereditary HR with calciuria types.


Results in 3-4 weeks.

Genes in the Skeletal Dysplasia with Abnormal Mineralization Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
B4GALT7Ehlers-Danlos syndrome, progeroid formAR88
CLCN5Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis, Hypophosphatemic rickets,, Nephrolithiasis, I, Dent diseaseXL37255
COL1A1Ehlers-Danlos syndromeAD120883
COL1A2Ehlers-Danlos syndrome, cardiac valvular formAD79473
COL3A1Ehlers-Danlos syndromeAD452617
COL5A1Ehlers-Danlos syndromeAD43133
COL5A2Ehlers-Danlos syndromeAD1223
CYP27B1Vitamin D-dependent ricketsAR2075
ENPP1Arterial calcification, Hypophosphatemic ricketsAR1772
FBN1MASS syndrome, Shprintzen-Goldberg syndrome, Marfan syndromeAD5192056
FGF23Tumoral calcinosis, hyperphosphatemic, Hypophosphatemic ricketsAD/AR716
P3H1Osteogenesis imperfectaAR1233
PHEXHypophosphatemic ricketsXL75411
PLOD2Bruck syndromeAR411
SLC34A3Hypophosphatemic rickets with hypercalciuriaAR1036
SLC39A13Spondylodysplastic Ehlers-Danlos syndromeAR27
SOX9Campomelic dysplasia, 46,XY sex reversalAD24135
TNFRSF11AFamilial expansile osteolysis, Paget disease of boneAD/AR822
TNFRSF11BPaget disease of bone, juvenileAR821
VDRVitamin D-dependent ricketsAD/AR1767

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 (; HGMD, refers to a 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 CDG ( or Orphanet ( databases.

Blueprint Genetics offers a comprehensive skeletal dysplasia with abnormal mineralization panel that covers classical genes associated with hypophosphatasia, hypophosphatemic rickets and osteogenesis imperfecta. 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 (, the NHLBI GO Exome Sequencing Project (ESP;, the Exome Aggregation Consortium (ExAC;, ClinVar database of genotype-phenotype associations ( and the Human Gene Mutation Database ( The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (, Polyphen (, and Mutation Taster (

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


ICD codes

Commonly used ICD-10 codes when ordering the Skeletal Dysplasia with Abnormal Mineralization Panel

E83.31Hypophosphatemic rickets

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.