Osteogenesis Imperfecta and Hypophosphatasia (HPP) Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
3249 ALPL 81479,81479 Order Options and Pricing
BMP1 81479,81479
COL1A1 81408,81479
COL1A2 81408,81479
CREB3L1 81479,81479
CRTAP 81479,81479
FKBP10 81479,81479
IFITM5 81479,81479
LRP5 81406,81479
MBTPS2 81479,81479
NBAS 81479,81479
NTRK1 81479,81479
P3H1 81479,81479
PLOD2 81479,81479
PLS3 81479,81479
PPIB 81479,81479
SEC24D 81479,81479
SERPINF1 81479,81479
SERPINH1 81479,81479
SLC2A2 81479,81479
SP7 81479,81479
SPARC 81479,81479
TAPT1 81479,81479
TENT5A 81479,81479
TMEM38B 81479,81479
WNT1 81479,81479
XYLT2 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
3249Genes x (27)81479 81406, 81408, 81479 $960 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous skeletal disorder characterized by frequent bone fractures with or without minimal trauma. Clinical signs of OI can range from mild to severe. In addition to bone fractures, patients may have scoliosis, bowing of long bones, short stature, blue sclera, hearing loss, dentin defects, muscle weakness or joint laxity. Bone fractures and bowing of long bones in osteogenesis imperfecta patients may occur prenatally in severe OI cases, and hearing loss may occur in ~50% of type I OI patients by 40-years-old (https://emedicine.medscape.com/article/947588-overview). The incidence is approximately 6/100,000 (van Dijk et al. 2012. PubMed ID: 21829228). Approximately 90% of clinically diagnosed OI is caused by pathogenic variants in the COL1A1 and COL1A2 genes, while ~10% is caused by pathogenic variants in the BMP1, CREB3L1, CRTAP, FKBP10, IFITM5, P3H1(also called LEPRE1), PLOD2, PPIB, SEC24D, SERPINF1, SERPINH1, SP7, WNT1, TMEM38B, NTRK1 and other undefined genes (van Dijk and Sillence. 2014. PubMed ID: 24715559; Valadares et al. 2014. PubMed ID: 25046257; Moosa et al. 2015. PubMed ID: 26467156; Caparros-Martin et al. 2017. PubMed ID: 28116328).

Hypophosphatasia (HPP) 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, including: (1) perinatal lethal HPP characterized by respiratory insufficiency and hypercalcemia; (2) perinatal benign HPP with prenatal skeletal manifestations that slowly resolve into the milder childhood or adult form; (3) infantile HPP with onset between birth and age six months of rickets; (4) childhood HPP that ranges from low bone mineral density for age with unexplained fractures to rickets; (5) adult HPP characterized by early loss of adult dentition and stress fractures and pseudofractures of the lower extremities in middle age; and (6) odontohypophosphatasia characterized by premature exfoliation of primary teeth and/or severe dental caries as an isolated finding or as part of the above forms of HPP (Mornet and Nunes. 2016. PubMed ID: 20301329). HPP is caused by pathogenic variants in the ALPL gene.

Genetics

Genes Related to Autosomal Dominant OI: Pathogenic variants in the COL1A1, COL1A2, and IFITM5 genes cause autosomal dominant OI. More than 95% of pathogenic variants in the COL1A1 and COL1A2 genes are nucleotide substitutions or small deletions or insertions, 1% -2% of COL1A1 and COL1A2 pathogenic variants are larger deletions or insertions (van Dijk and Sillence. 2014. PubMed ID: 24715559; Steiner and Basel. 2019. PubMed ID: 20301472). Almost all perinatal lethal OI are caused by de novo variants in COL1A1 and COL1A2 (Steiner and Basel. 2019. PubMed ID: 20301472).

Genes Related to Autosomal Recessive OI: Pathogenic variants in the BMP1, CREB3L1, CRTAP, FKBP10, P3H1 (also called LEPRE1), PLOD2, PPIB, SEC24D, SERPINF1, SERPINH1, SP7, TMEM38B, TENT5A, MBTPS2, NBAS, SLC2A2, SPARC, TAPT1 and NTRK1 genes cause autosomal recessive OI.

Recently, pathogenic variants in the TENT5A (Doyard. 2018. PubMed ID: 29358272), NBAS (Balasubramanian et al. 2017. PubMed ID: 27789416), SLC2A2 (Caparros-Martin et al. 2017. PubMed ID: 28116328), SPARC (Mendoza-Londono et al. 2015. PubMed ID: 26027498), and TAPT1 (Symoens et al. 2015. PubMed ID: 26365339) have been reported in a few patients with autosomal recessive osteogenesis imperfecta.

Pathogenic variants in the XYLT2 gene have been reported in patients with autosomal recessive Spondyloocular syndrome (Taylan et al. 2016. PubMed ID: 26987875), which is characterized by spinal and long bone fractures, osteoporosis, cataract, hearing impairment, cardiac septal defects, and learning difficulties.

Genes related to both autosomal dominant and autosomal recessive OI: WNT1 pathogenic variants mainly cause autosomal recessive OI, but WNT1 has also been reported to be associated with autosomal dominant OI in rare cases.

Pathogenic variants in LRP5 cause autosomal recessive osteoporosis-pseudoglioma syndrome, autosomal dominant Osteopetrosis, type1 and autosomal bone mineral density variability 1.

Genes Related to X-linked OI: Pathogenic variants in PLS3 cause X-linked Bone mineral density QTL18 osteoporosis.

Pathogenic variants in MBTPS2 were reported to be associated with X-linked osteogenesis imperfecta (Lindert et al. 2016. PubMed ID: 27380894).

Autosomal dominant and autosomal recessive Hypophosphatasia are caused by pathogenic variants in the ALPL gene. The majority of ALPL variants are inherited, in rare cases, de novo variants were reported (Mornet and Nunes. 2016. PubMed ID: 20301329; Taillandier et al. 2005. PubMed ID: 15671102).

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Clinical Sensitivity - Sequencing with CNV PGxome

Pathogenic variants in COL1A1 and COL1A2 were found in 90% of individuals with Osteogenesis Imperfecta (OI) types I, II, III, or IV (Steiner and Basel. 2019. PubMed ID: 20301472). A recent study reported that COL1A1 and COL1A2 pathogenic variants were identified in 56% (14/35) and 44% (11/35) of OI cases, respectively (Stephen et al. 2014. PubMed ID: 24668929).

Only one large homozygous deletion involving CREB3L1 was reported in a patient affected with autosomal recessive OI (Symoens et al. 2013. PubMed ID: 24079343).

CRTAP pathogenic variants were identified in 1 out of 10 clinically diagnosed autosomal recessive OI families (Caparrós-Martin et al. 2013. PubMed ID: 23613367).

In one publication, FKBP10 pathogenic variants were identified in 21 families affected with either autosomal recessive OI or Bruck syndrome (Schwarze et al. 2013. PubMed ID: 22949511). The pathogenic variants detection rate should be high, because all reported FKBP10 pathogenic variants are point variants or small deletions and insertions, which can be detected by sequencing.

So far, only two pathogenic IFITM5 variants have been reported (Guillén-Navarro et al. 2014. PubMed ID: 24478195). The clinical sensitivity should be high for patients with clinically diagnosed OI type V. The c.-14C>T IFITM5 pathogenic variant was found in almost all clinically diagnosed OI Type V patients tested (Lazarus et al. 2014. PubMed ID: 24674092; Human Gene Mutation Database).

P3H1 pathogenic variants were identified in 2 out of 10 clinically diagnosed autosomal recessive OI families (Caparrós-Martin et al. 2013. PubMed ID: 23613367).

SERPINF1 pathogenic variants were identified in 3 out of 10 clinically diagnosed autosomal recessive OI families (Caparrós-Martin et al. 2013. PubMed ID: 23613367).

SERPINH1 pathogenic variants were identified in 1 out of 30 individuals who tested negative for pathogenic variants in COL1A1, COL1A2, CRTAP and LEPRE1 (Christiansen et al. 2010. PubMed ID: 20188343).

So far, only one pathogenic SP7 pathogenic variant, a small deletion, has been reported (Lapunzina et al. 2010. PubMed ID: 20579626).

WNT1 pathogenic variants were reported in 5 out of 12 OI families in which no pathogenic variants in other OI-related genes were found (Keupp et al. 2013. PubMed ID: 23499309).

PLOD2 pathogenic variants were identified in 4 out of 6 clinically diagnosed, consanguineous, unrelated Egyptian families affected with Bruck syndrome type 2 (Puig-Hervás et al. 2012. PubMed ID: 22689593).

Recently, a homozygous missense variant in the NTRK1 gene has been reported in one patient from a consanguineous family with OI-related features (Caparros-Martin et al. 2017. PubMed ID: 28116328).

Sequencing of ALPL is predicted to detect pathogenic variants in 95% of cases with severe perinatal and infantile HPP. In milder forms, the detection rate is difficult to estimate. Overall, ~50% of cases with a clinical diagnosis of HPP have two ALPL pathogenic variants and ~40%-45% have one pathogenic variant. The milder the disease, the higher the proportion in which only one ALPL pathogenic variant is detected (Mornet and Nunes. 2016. PubMed ID: 20301329).

To our knowledge, only a few large deletions involving ALPL have been reported (Mornet and Nunes. 2016. PubMed ID: 20301329). Large deletions account for 2.2% of reported ALPL pathogenic variants in an ALPL mutation database (http://www.sesep.uvsq.fr/03_hypo_mutations.php).

Only two large deletions to date have been reported in LRP5 for osteoporosis-pseudoglioma syndrome (Human Gene Mutation Database).

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.9% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Candidates for this test include patients with a clinical presentation of Osteogenesis imperfecta, or hypophosphatasia.

Diseases

Name Inheritance OMIM ID
Adult Hypophosphatasia AD,AR 146300
Bone Mineral Density QTL18, Osteoporosis XL 300910
Bruck Syndrome 2 AR 609220
Caffey Disease AD 114000
Childhood Hypophosphatasia AR 241510
Cole-Carpenter Syndrome 2 AR 616294
Ehlers-Danlos Syndrome, Autosomal Recessive, Cardiac Valvular Form AR 225320
Ehlers-Danlos Syndrome, Type 1 AD 130000
Ehlers-Danlos Syndrome, Type VIIA and VIIB AD 130060
Fanconi-Bickel Syndrome AR 227810
Ichthyosis Follicularis Atrichia Photophobia Syndrome XL 308205
Infantile Hypophosphatasia AR 241500
Infantile Liver Failure Syndrome 2 AR 616483
Olmsted syndrome, X-linked XL 300918
Osteochondrodysplasia, complex lethal, Symoens-Barnes-Gistelinck type AR 616897
Osteogenesis Imperfecta Type III AD 259420
Osteogenesis Imperfecta, Type I AD 166200
Osteogenesis Imperfecta, Type II AD 166210
Osteogenesis Imperfecta, Type IV AD 166220
Osteogenesis Imperfecta, Type IX AR 259440
Osteogenesis imperfecta, type V AD 610967
Osteogenesis Imperfecta, Type VI AR 613982
Osteogenesis Imperfecta, Type VII AR 610682
Osteogenesis Imperfecta, Type VIII AR 610915
Osteogenesis Imperfecta, Type X AR 613848
Osteogenesis Imperfecta, Type XI AR 610968
Osteogenesis Imperfecta, Type XII AR 613849
Osteogenesis Imperfecta, Type XIII AR 614856
Osteogenesis Imperfecta, Type XIV AR 615066
Osteogenesis Imperfecta, Type XV AR 615220
Osteogenesis Imperfecta, Type XVII AR 616507
Osteogenesis imperfecta, type XVIII AR 617952
Osteopetrosis Autosomal Dominant Type 1 AD 607634
Pseudoxanthoma Elasticum AR 264800
Short stature, Optic nerve atrophy, and Pelger-Huet anomaly AR 614800
Spondyloocular syndrome AR 605822

Related Test

Name
PGxome®

Citations

  • Balasubramanian et al. 2017. PubMed ID: 27789416
  • Caparrós-Martin et al. 2013. PubMed ID: 23613367
  • Caparros-Martin et al. 2017. PubMed ID: 28116328
  • Christiansen et al. 2010. PubMed ID: 20188343
  • Doyard. 2018. PubMed ID: 29358272
  • Guillén-Navarro et al. 2014. PubMed ID: 24478195
  • Human Gene Mutation Database (Bio-base).
  • Keupp et al. 2013. PubMed ID: 23499309
  • Lapunzina et al. 2010. PubMed ID: 20579626
  • Lazarus et al. 2014. PubMed ID: 24674092
  • Lindert et al. 2016. PubMed ID: 27380894
  • Mendoza-Londono et al. 2015. PubMed ID: 26027498
  • Moosa et al. 2015. PubMed ID: 26467156
  • Mornet and Nunes. 2016. PubMed ID: 20301329
  • Puig-Hervás et al. 2012. PubMed ID: 22689593
  • Schwarze et al. 2013. PubMed ID: 22949511
  • Steiner and Basel. 2019. PubMed ID: 20301472
  • Stephen et al. 2014. PubMed ID: 24668929
  • Symoens et al. 2013. PubMed ID: 24079343
  • Symoens et al. 2015. PubMed ID: 26365339
  • Taillandier et al. 2005. PubMed ID: 15671102
  • Taylan et al. 2016. PubMed ID: 26987875
  • Valadares et al. 2014. PubMed ID: 25046257
  • van Dijk and Sillence. 2014. PubMed ID: 24715559
  • van Dijk et al. 2012. PubMed ID: 21829228

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

loading Loading... ×

ORDER OPTIONS

View Ordering Instructions

1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Total Price: $
×
Copy Text to Clipboard
×