Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene

Otospondylomegaepiphyseal dysplasia (OSMED) is an autosomal recessive skele tal dysplasia accompanied by severe hearing loss. The phenotype overlaps th at of the autosomal dominant disorders-Stickler and Marshall syndromes-but can be distinguished by disproportionately short limbs, severe hearing loss , and lack of ocular involvement. In one family with OSMED, a homozygous Gl y-->Arg substitution has been described in COL11A2, which codes for the alp ha 2 chain of type XI collagen. We report seven further families with OSMED . All affected individuals had a remarkably similar phenotype: profound sen sorineural hearing loss, skeletal dysplasia with limb shortening and large epiphyses, cleft palate, an extremely aat face, hypoplasia of the mandible, a short nose with anteverted nares, and a nat nasal bridge. We screened af fected individuals for mutations in COL11A2 and found different mutations i n each family. Individuals from four families, including three with consang uineous parents, were homozygous for mutations. Individuals from three othe r families, in whom parents were non-consanguineous, were compound heterozy gous. Of the 10 identified mutations, 9 are predicted to cause premature te rmination of translation, and 1 is predicted to cause an in-frame deletion, We conclude that the OSMED phenotype is highly homogenous and results from homozygosity or compound heterozygosity for COL11A2, mutations, most of wh ich are predicted to cause complete absence of alpha 2(XI) chains.