ACAN was first reported in relation to autosomal semidominant ACAN-related short stature spectrum in 2005 (Gleghorn et al., PMID: 16080123). ACAN-related short stature spectrum is characterized by short stature with or without advanced bone age, and osteochondritis dissecans. Spondyloepiphyseal dysplasia, Kimberley type (SEDK) may be present in the case of heterozygous alleles. In the case of compound heterozygous or homozygous alleles, spondyloepimetaphyseal dysplasia, aggrecan type will be present. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism. Therefore, the following disease entities have been lumped into one disease entity, SEDK (OMIM:608361), short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (OMIM:165800), and spondyloepimetaphyseal dysplasia, aggrecan type (OMIM:612813). Twelve variants (missense, nonsense, and frameshift) that have been reported in eleven probands in seven publications (PMIDs: 16080123, 19110214, 24762113, 25741789, 29464738, 30124491, 35620465) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by expression studies, biochemical function, and animal models (PMIDs: 7524681, 23019016, 9192671). ACAN is expressed in chondrocytes and critical to the developing skeleton and cartilage function (PMIDs: 7524681, 23019016). Additionally, heterozygous and homozygous ACAN defective mice were observed to have severe short stature in addition to other radiographic abnormalities. Similarly, a chicken with nanomelia has been described with homozygous nonsense variants in aggrecan (PMID:7827752). In summary, there is definitive evidence supporting the relationship between ACAN and autosomal semidominant ACAN-related short stature spectrum. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date May 7, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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