In human, heterozygous ACAN variants have been identified in SEDK, and autosomal dominant familial osteochondritis dissecans, whereas homozygous mutations result in SEMDAG and macrocephaly with multiple epiphyseal dysplasia and distinctive facies.9, 10, 21 All missense mutations in G3 domain result in broad spectrum of aggrecanopathies (Fig. 4), this clinical heterogeneity resulted from presence of different disease mechanisms or modifier genes. This evidence concerns the gene ACAN and spondyloepimetaphyseal dysplasia, aggrecan type.