Table 1.

Molecular Genetic Testing Used in Autosomal Dominant Multiple Epiphyseal Dysplasia

Gene 1, 2Proportion of Autosomal Dominant MED Attributed to Pathogenic Variants in Gene 3, 4Proportion of Pathogenic Variants 5 Detectable by Method
Sequence analysis 6Gene-targeted deletion/duplication analysis 7
COL9A1 10%100% 8None reported 9
COL9A2 100% 8None reported 9
COL9A3 100% 8None reported 9
COMP 50%100% 8None reported 9
MATN3 20%100% 8Unknown 10
Unknown 11~20%?NA

Genes are listed in alphabetic order.


In individuals with autosomal dominant MED in whom a pathogenic variant in one of the five confirmed genes has been identified. However, the relative proportions are different depending on ethnicity. For example, a recent study by the European Skeletal Dysplasia Network (ESDN) [Jackson et al 2012] found that in 56 individuals with molecularly confirmed MED, COMP pathogenic variants accounted for 66%, MATN3 for 24%, COL9A2 for 8%, and COL9A3 for 2%. In contrast, a recent study of a Korean cohort identified pathogenic variants in 55 individuals as follows: COMP (43%), MATN3 (55%), and COL9A2 (2%) [Kim et al 2011]. This is in close agreement with a Japanese study that identified pathogenic variants in 19 individuals with MED: COMP (37%), MATN3 (47%), COL9A2 (11%), and COL9A3 (5%). The high prevalence of MATN3 pathogenic variants in these latter populations is believed to be the result of a common founder variant (p.Arg121Trp), but this variant is also common in European populations. None of the three studies identified pathogenic variants in COL9A1.


The proportion of COL9A1-3, COMP, and MATN3 pathogenic variants found in persons with MED is not well established. Previous studies have suggested frequencies of 10%-36% for COMP [Jakkula et al 2005, Kennedy et al 2005b], 10% for MATN3, and 5% for the type IX collagen genes [Briggs & Chapman 2002, Jackson et al 2004]. However, in a later study by the ESDN the proportion of MED caused by pathogenic variants in COMP increased to 81% when a strict clinical-radiographic review was undertaken before molecular genetic testing was performed [Zankl et al 2007]. The success of this approach was confirmed by Kim et al [2011], when pre-selection resulted in a variant detection rate of 87%.


See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


All variants reported to date have been detectable by sequence analysis.


No whole-gene deletions or duplications involving COL9A1, COL9A2, COL9A3, or COMP have been reported to cause autosomal dominant MED.


No data on detection rate of gene-targeted deletion/duplication analysis are available.


Pathogenic variants remain undetected in approximately 20% of individuals with MED.

From: Multiple Epiphyseal Dysplasia, Autosomal Dominant

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