Chronic Joint Pain and Dysfunction via the MMP13 Gene
Summary and Pricing 
Test Method
Exome Sequencing with CNV Detection
| Test Code | Test Copy Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 8417 | MMP13 | 81479 | 81479,81479 | $990 | Order Options and Pricing |
Pricing Comments
Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information.
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).
Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).
The Sanger Sequencing method for this test is NY State approved.
For Sanger Sequencing click here.Turnaround Time
3 weeks on average for standard orders or 2 weeks on average for STAT orders.
Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.
Targeted Testing
For ordering sequencing of targeted known variants, go to our Targeted Variants page.
Clinical Features and Genetics
Clinical Features
Genetic bone disorders are characterized by defective growth and modeling of the spine, long bones (e.g., femur, tibia, or both), and cartilage, as well as joint pain. These disorders include several skeletal diseases such as spondyloepimetaphyseal dysplasias (SEMDs), metaphyseal anadysplasia (MAD), and osteoarthritis (OA). SEMDs generally feature moderate to severe metaphyseal changes, mild epiphyseal alterations, rhizomelic shortening of the lower limbs, pear-shaped vertebrae during childhood, and deformities in the genu varum or genu valgum (knock knee) secondary to bowing of the legs, resulting in short-trunk disproportionate dwarfism (Wynne-Davies and Hall 1982; Gertner et al. 1997; Isidor et al. 2013). The defects in modeling often improve during adolescence, although the affected individual usually remains shorter than age-matched children. The results of biochemical tests for skeletal homeostasis are usually normal, whereas radiologic and histopathologic assessment often indicates a primary abnormality involving growth plate development. MAD pertains to the early-onset regression category of metaphyseal dysplasia (Sobreira et al. 2014). A MAD diagnosis is often established during the first few months after birth when the long bones show irregular distal metaphyses. Individuals with MAD also present with hypoplastic femoral necks, with the edges of the metaphyses positioned in a vertical fashion (Verloes et al. 1990). The femoral shaft of individuals with MAD is generally bowed (MacDermot et al. 1991). Similar to SEMDs, MAD anomalies dissipate when a child reaches the age of two years old. MAD is also characterized by slight shortness and varus deformities involving the lower limbs, but stature remains unaffected. OA is a debilitating joint disorder that involves the mechanical disruption of the cartilage matrix, changes in bone mass, and localized inflammation (Mitchell et al. 1996). Inflammatory cytokines such as IL-1, IL-6, and TNF-alpha are expressed at the articular joint, causing inflammation and in turn stimulating the production of various matrix metalloproteinases (MMPs) (Goldring et al. 2011). Radiologic examination is considered the most reliable diagnostic and monitoring test for SEMDs, MAD, and OA.
Genetics
Chronic degenerative joint pain and dysfunction such as that observed in SMED, MAD, and OA is an autosomal dominant disorder caused by pathogenic sequence variants in the matrix metalloproteinase 13 (MMP13) gene. The MMP13 gene has been localized to chromosome 11q22.2 and consists of 10 exons that encode for a 471-amino acid polypeptide containing a sequence motif specific to the collagenase subfamily (Tardif et al. 1997).
The MMP13 gene is also known as collagenase-3 (CLG3), based on its identification as the third member of the collagenase family (Freije et al. 1994). MMP13 is commonly expressed by chondrocytes and is capable of degrading a wide range of collegenous and noncollagenous extracellular matrix macromolecules such as types 1-4 and 9-11 collagens, gelatin, fibrinogen, and laminin (Mitchell et al. 1996). Unlike most human MMPs, its expression is restricted in normal tissues and is often upregulated in pathologic conditions (Reboul et al. 1996; Goldring et al. 2011). Detection of MMP-13 is therefore often observed in situations where rapid collagen remodeling is required, which include fetal bone development and postnatal bone development (Dancevic and McCulloch 2014). In chronic disorders, MMP-13 is generally expressed at sites of excessive degradation of the extracellular matrix, which include the cartilage of patients with osteoarthritis, rheumatoid arthritis, and cancer (Freije et al. 1994; Mitchell et al. 1996; Reboul et al. 1996).
To date, a total of five pathogenic missense sequence variants have been reported to cause chronic degenerative joint pain and dysfunction (Kennedy et al. 2005; Lausch et al. 2009; Bonafe et al. 2014; Li et al. 2014). A small study involving two brothers diagnosed with MAD showed that both individuals possessed pathogenic sequence variants in the MMP13 gene (Li et al. 2015). In a study involving a three-generation family consisting of 12 family members, 5 affected individuals were determined to harbor causative sequence variants in the MMP13 gene (Bonafe et al. 2014). In a larger 4-generation family study comprising 32 family members (13 affected and 11 unaffected kin, and 8 unaffected spouses), 13 individuals carried pathogenic sequence variants in the MMP13 gene (Kennedy et al. 2005).
Clinical Sensitivity - Sequencing with CNV PGxome
A clinical study involving 13 patients diagnosed with MAD (belonging to five families) showed that all individuals harbored causative sequence variants in the MMP13 gene (Lausch et al. 2009).
Testing Strategy
This test provides full coverage of all coding exons of the MMP13 gene 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 full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).
Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).
Indications for Test
The ideal candidate for MMP13 testing should have been previously diagnosed with SMED, MAD, or OA by using radiologic examination.
The ideal candidate for MMP13 testing should have been previously diagnosed with SMED, MAD, or OA by using radiologic examination.
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| MMP13 | 600108 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Disease
| Name | Inheritance | OMIM ID |
|---|---|---|
| Spondyloepimetaphyseal Dysplasia, Missouri Type | AD | 602111 |
Citations
- Bonafé L, Liang J, Gorna MW, Zhang Q, Ha-Vinh R, Campos-Xavier AB, Unger S, Beckmann JS, Le Béchec A, Stevenson B, Giedion A, Liu X, Superti-Furga G, Wang W, Spahr A, Superti-Furga A. 2014. MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type. American Journal of Medical Genetics A. 164A(5): 1175-1179. PubMed ID: 24648384
- Dancevic CM, McCulloch DR. 2014. Current and emerging therapeutic strategies for preventing inflammation and aggrecanase-mediated cartilage destruction in arthritis. Arthritis Research and Therapy. 16(5): 429. PubMed ID: 25606593
- Freije JM, Díez-Itza I, Balbín M, Sánchez LM, Blasco R, Tolivia J, López-Otín C. 1994. Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas. Journal of Biological Chemistry. 269(24): 16766-16763. PubMed ID: 8207000
- Gertner JM, Whyte MP, Dixon PH, Pang JT, Trump D, Pearce SH, Wooding C, Thakker RV. 1997. Linkage studies of a Missouri kindred with autosomal dominant spondyloepimetaphyseal dysplasia (SEMD) indicate genetic heterogeneity. Journal of Bone and Mineral Research. 12(8): 1204-1209. PubMed ID: 9258750
- Goldring MB, Otero M, Plumb DA, Dragomir C, Favero M, El Hachem K, Hashimoto K, Roach HI, Olivotto E, Borzì RM, Marcu KB. 2011. Roles of inflammatory and anabolic cytokines in cartilage metabolism: signals and multiple effectors converge upon MMP-13 regulation in osteoarthritis. European Cells and Materials. 21: 202-220. PubMed ID: 21351054
- Goldring MB, Otero M, Plumb DA, Dragomir C, Favero M, El Hachem K, Hashimoto K, Roach HI, Olivotto E, Borzì RM, Marcu KB. 2011. Roles of inflammatory and anabolic cytokines in cartilage metabolism: signals and multiple effectors converge upon MMP-13 regulation in osteoarthritis. Europeran Cells and Materials. 21:202-220.
- Isidor B, Geffroy L, de Courtivron B, Le Caignec C, Thiel CT, Mortier G, Cormier-Daire V, David A, Toutain A. 2013. A new form of severe spondyloepimetaphyseal dysplasia: Clinical and radiological characterization. American Journal of Medical Genetics A. 161A(10): 2645-26451. PubMed ID: 23956136
- Kennedy AM, Inada M, Krane SM, Christie PT, Harding B, López-Otín C, Sánchez LM, Pannett AA, Dearlove A, Hartley C, Byrne MH, Reed AA, Nesbit MA, Whyte MP, Thakker RV. 2005. MMP13 mutation causes spondyloepimetaphyseal dysplasia, Missouri type (SEMD(MO). Journal of Clinical Investigations. 115(10): 2832-2842. PubMed ID: 16167086
- Lausch E, Keppler R, Hilbert K, Cormier-Daire V, Nikkei S, Nishimura G, Unger S, Spranger J, Superti-Furga A, Bernhard Z. 2009. Mutations in MMP9 and MMP13 determine the mode of inheritance and the clinical spectrum of metaphyseal anadysplasia. The American Journal of Human Genetics. 85: 168-178. PubMed ID: 19615667
- Lausch E, Keppler R, Hilbert K, Cormier-Daire V, Nikkel S, Nishimura G, Unger S, Spranger J, Superti-Furga A, Zabel B. 2009. Mutations in MMP9 and MMP13 determine the mode of inheritance and the clinical spectrum of metaphyseal anadysplasia. American Journal of Human Genetics. 85(2): 168-178.
- Li D, Weber DR, Deardorff MA, Hakonarson H, Levine MA. 2015. Exome sequencing reveals a nonsense mutation in MMP13 as a new cause of autosomal recessive metaphyseal anadysplasia. European Journal of Human Genetics. 23(2): 264-266. PubMed ID: 24781753
- MacDermot KD, Winter RM, Wigglesworth JS, Strobel S. 1991. Short stature/short limb skeletal dysplasia with severe combined immunodeficiency and bowing of the femora: report of two patients and review. Journal of Medical Genetics. 28(1): 10-17. PubMed ID: 1999827
- Mitchell PG, Magna HA, Reeves LM, Lopresti-Morrow LL, Yocum SA, Rosner PJ, Geoghegan KF, Hambor JE. 1996. Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. Journal of Clinical Investigations. 97(3): 761-768. PubMed ID: 8609233
- Mitchell PG1, Magna HA, Reeves LM, Lopresti-Morrow LL, Yocum SA, Rosner PJ, Geoghegan KF, Hambor JE. 1996. Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. Journal of Clinical Investigations. 97(3): 761-768.
- Reboul P, Pelletier JP, Tardif G, Cloutier JM, Martel-Pelletier J. 1996. The new collagenase, collagenase-3, is expressed and synthesized by human chondrocytes but not by synoviocytes. A role in osteoarthritis. Journal of Clinical Investigations. 97(9): 2011-2019. PubMed ID: 8621789
- Sobreira N, Modaff P, Steel G, You J, Nanda S, Hoover-Fong J, Valle D, Pauli RM. 2015. An anadysplasia-like, spontaneously remitting spondylometaphyseal dysplasia secondary to lamin B receptor (LBR) gene mutations: further definition of the phenotypic heterogeneity of LBR-bone dysplasias. American Journal of Medical Genetics A. 167A(1): 159-163. PubMed ID: 25348816
- Tardif G, Pelletier JP, Dupuis M, Hambor JE, Martel-Pelletier J. Cloning, sequencing and characterization of the 5 PubMed ID: 9173871
- Verloes A, Van Maldergem L, de Marneffe P, Dufier JL, Maroteaux P. 1990. Microspherophakia-metaphyseal dysplasia: a PubMed ID: 2395168
- Wynne-Davies R, Hall C. 1982. Two clinical variants of spondylo-epiphysial dysplasia congenita. Journal of Bone and Joint Surgery British Volume. 64(4): 435-441. PubMed ID: 6807992
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