Multiple Epiphyseal Dysplasia Panel

Multiple epiphyseal dysplasia (MED) is a clinically and genetically heterogeneous chondrodysplasia with either autosomal dominant or recessive inheritance. Dominant MED (ADMED) occurs early in childhood and usually involves pain in the hips and/or knees after exercise. Some patients may have a waddling gait. Adult height can be in the lower range of normal or mildly shortened. The limbs are relatively short in comparison to the trunk. Other features may include progressive pain and joint deformity which can lead to early-onset osteoarthritis. ADMED is caused by pathogenic variants in the COMP, MATN3, COL9A1, COL9A2, COL9A3 and COL2A1 genes (Briggs et al. 2019. PubMed ID: 20301302).

Recessive MED (ARMED) is characterized by joint pain (usually in the hips or knees) occurring in late childhood. Malformations of hands, feet, and knees; and scoliosis may also be observed. Height is usually within the normal range prior to puberty; Adult height can range from 150 to 180 cm. Pathogenic variants in the SCL26A2 gene have been reported in patients with ARMED (Hauer et al. 2018. PubMed ID: 29758562; Bonafé et al. 2014. PubMed ID: 20301483). Pathogenic variants in the CANT1, DDR2 and UFSP2 gene have been reported in ARMED and autosomal recessive spondylo-meta-epiphyseal dysplasia (Balasubramanian et al. 2017. PubMed ID: 28742282; Bargal et al. 2009. PubMed ID: 19110212; Di Rocco et al 2018. PubMed ID: 28892125; Watson et al. 2015. PubMed ID: 26428751).

Pathogenic variants in COMP, MATN3 and type IX collagen genes (COL9A1, COL9A2 and COL9A3) account for 70% , ~20% and ~10% of ADMED, respectively (Jackson et al. 2012. PubMed ID: 21922596; Briggs et al. 2019. PubMed ID: 20301302). Pathogenic variants in SLC26A2 mainly cause autosomal recessive diastrophic dysplasia and a few have been reported in patients with ARMED and other conditions (Rossi and Superti-Furga. 2001. PubMed ID: 11241838; Bonafe et al. 2015. PubMed ID:26394607). In addition to MED, pathogenic variants in these genes also cause other skeletal dysplasia disorders. These skeletal disorders have overlapping clinical features with MED, which causes difficulties in reaching a correct clinical diagnosis. Molecular diagnosis of the skeletal dysplasia subtypes is also complex because extensive genetic heterogeneity exists for each disorder (Bonafe et al. 2015. PubMed ID:26394607). Considering the clinical and genetic heterogeneity, a molecular testing approach that interrogates all known MED genes is highly recommended.

Pathogenic variants in CANT1 have been mainly reported in patients with autosomal recessive desbuquois dysplasia (Huber et al. 2009. PubMed ID: 19853239). To date, only two homozygous missense variants were reported in two families with MED (Balasubramanian et al. 2017. PubMed ID: 28742282).

Pathogenic variants in DDR2 have been reported in patients with autosomal recessive spondylo-meta-epiphyseal dysplasia (Bargal et al. 2009. PubMed ID: 19110212).

A few missense variants in UFSP2 have been reported in patients with autosomal dominant Spondyloepimetaphyseal dysplasia (Di Rocco et al 2018. PubMed ID: 28892125; Watson et al. 2015. PubMed ID: 26428751).

See individual gene test descriptions for information on molecular biology of gene products.

Causative variants in COMP, MATN3 and type IX collagen genes (COL9A1, COL9A2 and COL9A3) account for 70% , ~20% and ~10% of dominant Multiple Epiphyseal Dysplasia (MED), respectively (Jackson et al. 2012. PubMed ID: 21922596; Briggs et al. 2019. PubMed ID: 20301302). To date, only two missense variants in COL2A1 have been reported in MED patients (Jackson et al. 2012. PubMed ID: 21922596).

The sensitivity for large deletions and duplications may be low, because only a few cases with large deletions and insertions involving the COL9A3, COMP and COL2A1 genes have been reported (Van der Hout et al. 2002. PubMed ID: 12204008; Human Mutation Database).

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

This panel provides 100% 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. 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).