Bone Fragility and Fracture Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
12679 ALPI 81479,81479 Order Options and Pricing
ALPL 81479,81479
AMER1 81479,81479
ASCC1 81479,81479
B3GAT3 81479,81479
B4GALT7 81479,81479
BMP1 81479,81479
CA2 81479,81479
CDK5RAP2 81479,81479
CLCN5 81479,81479
CLCN7 81479,81479
COL1A1 81408,81479
COL1A2 81408,81479
CREB3L1 81479,81479
CRTAP 81479,81479
CYP27B1 81479,81479
CYP2R1 81479,81479
DMP1 81479,81479
ENPP1 81479,81479
FERMT3 81479,81479
FGF23 81404,81479
FKBP10 81479,81479
GALNT3 81479,81479
GPAA1 81479,81479
IFITM5 81479,81479
KL 81479,81479
LRP5 81406,81479
MBTPS2 81479,81479
MEPE 81479,81479
MESD 81479,81479
NBAS 81479,81479
NTRK1 81479,81479
OSTM1 81479,81479
P3H1 81479,81479
PHEX 81406,81479
PKDCC 81479,81479
PLOD2 81479,81479
PLS3 81479,81479
PPIB 81479,81479
PRKAR1A 81479,81479
SEC24D 81479,81479
SERPINF1 81479,81479
SERPINH1 81479,81479
SGMS2 81479,81479
SH3PXD2B 81479,81479
SLC29A3 81479,81479
SLC2A2 81479,81479
SLC34A1 81479,81479
SLC34A3 81479,81479
SLC5A6 81479,81479
SLC9A3R1 81479,81479
SNX10 81479,81479
SOST 81479,81479
SP7 81479,81479
SPARC 81479,81479
SQSTM1 81479,81479
TAPT1 81479,81479
TCIRG1 81479,81479
TENT5A 81479,81479
TGFB1 81479,81479
TMEM38B 81479,81479
TNFRSF11A 81479,81479
TNFRSF11B 81479,81479
TNFSF11 81479,81479
TRAF6 81479,81479
TRIP4 81479,81479
VDR 81479,81479
WNT1 81479,81479
WNT3A 81479,81479
XYLT2 81479,81479
ZBTB20 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
12679Genes x (71)81479 81404, 81406, 81408, 81479 $1190 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.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

Targeted Testing

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

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

This panel includes the major genes associated with fragile bone conditions such as osteogenesis imperfecta, hypophosphatasia, inherited hypophosphatemic rickets,  inherited sclerosing bone dysplasias and Paget disease of bone.

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 of age (Genetics of Osteogenesis Imperfecta). 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 of rickets between birth and six months; (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.

Hypophosphatemic rickets is a condition of abnormal phosphate homeostasis characterized by renal phosphate wasting, hypophosphatemia, and rickets/osteomalacia. Patients usually manifest bone deformity such as bowed legs after 2 years old. Patients will also develop pain in the pelvis and legs with age (Bastepe and Jüppner. 2008. PubMed ID: 18365315).

Sclerosing bone dysplasias is an abnormal accumulation of bone caused by defect of osteoblast or osteoclast regulation. It is a clinically and genetically heterogeneous group of diseases including several conditions such as, but not limited to steopetrosis, pyknodysostosis, osteopoikilosis, osteopathia striata, progressive diaphyseal dysplasia, multiple diaphyseal sclerosis, and hyperostosis corticalis generalisata (Ihde et al. 2011. PubMed ID: 22084176; Boulet et al. 2016. PubMed ID: 26898950).

Osteopetrosis (also called Marble bone disease) is a disorder of increased bone density and bone mass caused by malfunction of bone resorption. Some clinical features can occur in infancy (Aker et al. 2012. PubMed ID: 22499339). Affected patients are at high risk of frequent bone fractures, delayed healing, hip osteoarthritis and osteomyelitis. Some patients have vision loss, hearing loss, paralysis of facial muscles, and bone marrow abnormalities caused by abnormal dense bone structure. Other features include short stature, development delay, dental abnormalities, hepatosplenomegaly, intellectual disability, and epilepsy (Tolar et al. 2004. PubMed ID: 15625335; Del Fattore et al. 2008. PubMed ID: 17936098; Sobacchi et al. 2013. PubMed ID: 23877423). The estimated incidence of this condition is 1:20,000 (autosomal dominant) to 1:250,000 (autosomal recessive) births (Palagano et al. 2018. PubMed ID: 29335834). It can be inherited in autosomal dominat, autosomal recessive and rarely in X-linked manners. The major genes involved are CLCN7, LRP5, TCIRG1, TNFSF11, CA2, OSTM1, SNX10 and TNFRSF11A.

Paget disease of bone (PDB) is the second most common metabolic bone disorder affecting ~2% of the population aged >40 years. It is chronic, non-inflammatory bone condition caused by increased bone resorption and new bone formation within lesion sites. The disorder is characterized by focal areas of increased and disorganized bone turnover, leading to bone pain, deformity, pathological fracture, neurological complications, and an increased risk of osteosarcoma (Laurin et.al. 2002. PubMed ID: 11992264; Wysiński and Krajewska-Włodarczyk. 2019. PubMed ID: 31462833; Nebot Valenzuela and Pietschmann. 2017. PubMed ID: 27600564). The axial skeleton is preferentially affected. Common sites of involvement include the pelvis (70% of cases), femur (55%), lumbar spine (53%), skull (42%), and tibia (32%) (Ralston et al. 2008. PubMed ID: 18620951). PDB can be inherited or sporadic, with the inherited form accounting for about one-third of patients with PDB (Michou. 2006. PubMed ID: 16574459).  The major genes are involved are SQSTM1 and TNFRSF11B. 

Molecular genetic testing is advantageous to establish an accurate diagnosis for individuals with weakened bone and bone fracture conditions.

Genetics

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).

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).

X-linked Hypophosphatemic Rickets is mainly caused by deleterious variants in the PHEX gene and rarely caused by deleterious variants in CLCN5 (Hauer et al. 2018. PubMed ID: 29758562). Approximately 83% of female sporadic PHEX-related X-linked Hypophosphatemic ricket cases had a de novo variant (Durmaz et al. 2013. PubMed ID: 23079138).

Osteopetrosis are mainly caused by pathogenic variants in the following genes: CLCN7, LRP5, TCIRG1, TNFSF11, CA2, OSTM1, SNX10, and TNFRSF11A.

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

Testing Strategy

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

This panel typically provides 98.7% 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).

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 were identified in 56% (14/35) and 44% (11/35) of the OI cases, respectively (Stephen et al. 2014. PubMed ID: 24668929).

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).

In one study on hypophosphatemic rickets, PHEX pathogenic variants were identified 93 out of 118 probands (79%) (Gaucher et al. 2009. PubMed ID: 19219621). In another study, PHEX pathogenic variants were identified in 20 out of 24 unrelated probands (83%); three of these probands carried a large deletion or duplication detected by MLPA (Beck-Nielsen et al. 2012. PubMed ID: 22695891).

Pathogenic variants in the TCIRG1 and CLCN7 genes explain ~50% and 17% of autosomal recessive osteopetrosis, respectively (Palagano et al. 2018. PubMed ID: 29335834). In one study, SNX10 pathogenic variants were identified in 4% of 310 clinically diagnosed osteopetrosis cases (Pangrazio et al. 2013).

Indications for Test

Candidates for this test include patients with a clinical presentation of osteogenesis imperfecta, hypophosphatasia, inherited hypophosphatemic rickets, sclerosing bone dysplasias, osteopetrosis, signs of weakened bone, and bone fracture.

Diseases

Name Inheritance OMIM ID
Acrodysostosis AD 101800
Adult Hypophosphatasia AD,AR 146300
Arterial Calcification Of Infancy AR 208000
Autosomal Recessive Hypophosphatemic Bone Disease AR 241530
Bone Mineral Density QTL18, Osteoporosis XL 300910
Bruck Syndrome 2 AR 609220
Caffey Disease AD 114000
Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia AD 126550
Camurati-Engelmann Disease AD 131300
Childhood Hypophosphatasia AR 241510
Cole-Carpenter Syndrome 2 AR 616294
Craniodiaphyseal Dysplasia, Autosomal Dominant AD 122860
Dent Disease 1 XL 300009
Ehlers-Danlos Syndrome with Short Stature and Limb Anomalies AR 130070
Ehlers-Danlos Syndrome, Autosomal Recessive, Cardiac Valvular Form AR 225320
Ehlers-Danlos Syndrome, Type VIIA and VIIB AD 130060
Fanconi Renotubular Syndrome 2 AR 613388
Fanconi-Bickel Syndrome AR 227810
Frank Ter Haar Syndrome AR 249420
Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis 3 AD 616437
Glycosylphosphatidylinositol biosynthesis defect 15 AR 617810
Hyperphosphatasemia Tarda AR 239100
Hyperphosphatasemia With Bone Disease AR 239000
Hypophosphatemic Rickets, Autosomal Dominant AD 193100
Hypophosphatemic Rickets, X-Linked Dominant XL 307800
Hypophosphatemic Rickets, X-Linked Recessive XL 300554
Hypophosphatemic Vitamin D Refractory Rickets AR 241520
Ichthyosis Follicularis Atrichia Photophobia Syndrome XL 308205
Infantile Hypophosphatasia AR 241500
Leukocyte Adhesion Deficiency, Type III AR 612840
Multiple Joint Dislocations, Short Stature, Craniofacial Dysmorphism, and Congenital Heart Defects AR 245600
Muscular dystrophy, congenital, Davignon-Chauveau type AR 617066
Myopathy, distal, with rimmed vacuoles AD 617158
Nephrolithiasis/Osteoporosis, Hypophosphatemic, 1 AD 612286
Nephrolithiasis/Osteoporosis, Hypophosphatemic, 2 AD 612287
Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset AR 617145
Neurodegeneration, infantile-onset, biotin-responsive AR 618973
Osteitis Deformans AD 602080
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 XIX XL 301014
Osteogenesis Imperfecta, Type XV AR 615220
Osteogenesis Imperfecta, Type XVII AR 616507
Osteogenesis imperfecta, type XVIII AR 617952
Osteogenesis imperfecta, type XX AR 618644
Osteopathia Striata With Cranial Sclerosis XL 300373
Osteopetrosis Autosomal Dominant Type 1 AD 607634
Osteopetrosis Autosomal Dominant Type 2 AD 166600
Osteopetrosis Autosomal Recessive 1 AR 259700
Osteopetrosis Autosomal Recessive 2 AR 259710
Osteopetrosis Autosomal Recessive 4 AR 611490
Osteopetrosis Autosomal Recessive 5 AR 259720
Osteopetrosis Autosomal Recessive 7 AR 612301
Osteopetrosis With Renal Tubular Acidosis AR 259730
Osteopetrosis, Autosomal Recessive 8 AR 615085
Osteoporosis, early-onset, susceptibility to, autosomal dominant AD 615221
Paget Disease of Bone 3 AD 167250
Polyostotic Osteolytic Dysplasia, Hereditary Expansile AD 174810
Primary Autosomal Recessive Microcephaly 3 AR 604804
Primrose Syndrome AD 259050
Rhizomelic limb shortening with dysmorphic features AR 618821
Sclerosteosis AR 269500
Short stature, Optic nerve atrophy, and Pelger-Huet anomaly AR 614800
Spinal muscular atrophy with congenital bone fractures 1 AR 616866
Spinal muscular atrophy with congenital bone fractures 2 AR 616867
Spondyloocular syndrome AR 605822
Tumoral Calcinosis, Hyperphosphatemic, Familial AR 211900
Tumoral calcinosis, hyperphosphatemic, familial, 3 AR 617994
Vitamin D Hydroxylation-Deficient Rickets, Type 1B AR 600081
Vitamin D-Dependent Rickets, Type 1 AR 264700
Vitamin D-Dependent Rickets, Type 2 AR 277440

Related Test

Name
PGxome®

Citations

  • Aker et al. 2012. PubMed ID: 22499339
  • Bastepe and J├╝ppner. 2008. PubMed ID: 18365315
  • Beck-Nielsen et al. 2012. PubMed ID: 22695891
  • Boulet et al. 2016. PubMed ID: 26898950
  • Caparros-Martin et al. 2017. PubMed ID: 28116328
  • Del Fattore et al. 2008. PubMed ID: 17936098
  • Durmaz et al. 2013. PubMed ID: 23079138
  • Gaucher et al. 2009. PubMed ID: 19219621
  • Hauer et al. 2018. PubMed ID: 29758562
  • Ihde et al. 2011. PubMed ID: 22084176
  • Laurin et.al. 2002. PubMed ID: 11992264
  • Michou. 2006. PubMed ID: 16574459
  • Moosa et al. 2015. PubMed ID: 26467156
  • Mornet and Nunes. 2016. PubMed ID: 20301329
  • Nebot Valenzuela and Pietschmann. 2017. PubMed ID: 27600564
  • Palagano et al. 2018. PubMed ID: 29335834
  • Pangrazio et al. 2013. PubMed ID: 23280965
  • Ralston et.al. 2008. PubMed ID: 18620951
  • Sobacchi et al. 2013. PubMed ID: 23877423
  • Steiner and Basel. 2019. PubMed ID: 20301472
  • Stephen et al. 2014. PubMed ID: 24668929
  • Taillandier et al. 2005. PubMed ID: 15671102
  • Tolar et al. 2004. PubMed ID: 15625335
  • Valadares et al. 2014. PubMed ID: 25046257
  • van Dijk and Sillence. 2014. PubMed ID: 24715559
  • van Dijk et al. 2012. PubMed ID: 21829228
  • Wysinski and Krajewska-Wiodarczyk. 2019. PubMed ID: 31462833

Ordering/Specimens

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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.

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