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

Abstract

Otospondylomegaepiphyseal dysplasia (OSMED) is an autosomal recessive skeletal dysplasia accompanied by severe hearing loss. The phenotype overlaps that 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 Gly-->Arg substitution has been described in COL11A2, which codes for the alpha2 chain of type XI collagen. We report seven further families with OSMED. All affected individuals had a remarkably similar phenotype: profound sensorineural hearing loss, skeletal dysplasia with limb shortening and large epiphyses, cleft palate, an extremely flat face, hypoplasia of the mandible, a short nose with anteverted nares, and a flat nasal bridge. We screened affected individuals for mutations in COL11A2 and found different mutations in each family. Individuals from four families, including three with consanguineous parents, were homozygous for mutations. Individuals from three other families, in whom parents were nonconsanguineous, were compound heterozygous. Of the 10 identified mutations, 9 are predicted to cause premature termination 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 which are predicted to cause complete absence of alpha2(XI) chains.

Figure 1

Pedigrees of families with OSMED

Figure 2

Radiographs of femur (left), humerus (middle), and spinal column (right) of patient DII:2 at age 16 mo

Figure 3

Patient G:II1 at age 18 mo

Figure 4

Left, Radiograph of spine of patient G:II1 at age 3 mo. Middle, Radiograph of left arm of patient G:II2 at age 9 mo. Right, Radiograph of anteroposterior pelvis and hips of patient G:II1 at age 2 years 5 mo.

Figure 5

Sequencing of PCR products from a control subject (top) and individual C:II1 (bottom), for exon 31 of the COL11A2 gene. The underlined sequence in the top panel indicates the deletion, whereas the underlined sequence in the bottom panel indicates the insertion.