A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene

Abstract

Stickler syndrome is characterized by ophthalmic, articular, orofacial, and auditory manifestations. It has an autosomal dominant inheritance pattern and is caused by mutations in COL2A1, COL11A1, and COL11A2. We describe a family of Moroccan origin that consists of four children with Stickler syndrome, six unaffected children, and two unaffected parents who are distant relatives (fifth degree). All family members were clinically investigated for ear, nose, and throat; ophthalmologic; and radiological abnormalities. Four children showed symptoms characteristic of Stickler syndrome, including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia. We considered the COL9A1 gene, located on chromosome 6q13, to be a candidate gene on the basis of the structural association with collagen types II and XI and because of the high expression in the human inner ear indicated by cDNA microarray. Mutation analysis of the coding region of the COL9A1 gene showed a homozygous R295X mutation in the four affected children. The parents and four unaffected children were heterozygous carriers of the R295X mutation. Two unaffected children were homozygous for the wild-type allele. None of the family members except the homozygous R295X carriers had any signs of Stickler syndrome. Therefore, COL9A1 is the fourth identified gene that can cause Stickler syndrome. In contrast to the three previously reported Stickler syndrome-causing genes, this gene causes a form of Stickler syndrome with an autosomal recessive inheritance pattern. This finding will have a major impact on the genetic counseling of patients with Stickler syndrome and on the understanding of the pathophysiology of collagens. Mutation analysis of this gene is recommended in patients with Stickler syndrome with possible autosomal recessive inheritance.

Figure 1.

Pedigree of the family with autosomal recessive Stickler syndrome. Blackened symbols represent individuals with Stickler syndrome, and unblackened symbols represent individuals with a normal phenotype. Individual II.2 is a girl with hypophosphatemic rickets thought to be unrelated to Stickler syndrome. For all family members, the age when the clinical investigations were performed; the genotype; the PTA, or Fletcher index (FI), of the better ear; and the refractions for the right (R) and left (L) eyes are given below each symbol. For the affected individuals, extra clinical data on the ophthalmologic and radiological findings are also shown. wt = wild type; y = years.

Figure 2.

A, Pictures of the four affected family members. The height of all patients is <3rd percentile. They all have a relatively flat face. All patients wear glasses because of amblyopia with high myopia and astigmatism. They all have genua valga. B, Pictures of the six unaffected children. The facial features between unaffected and affected individuals are indistinguishable.

Figure 3.

A, Most-recent air conduction thresholds of the better ear for each of the four patients. The hearing loss is moderate to severe, with a mildly down-sloping audiogram. B, Air conduction thresholds of the better ear for each of the parents (bold lines) and unaffected children. The father has normal hearing for his age, with a bilateral sensorineural dip at 4,000 Hz, probably caused by known professional noise exposure. The mother has mild hearing loss of unknown cause. None of the unaffected children has hearing loss.

Figure 4.

A, Standard radiograph of the hands and wrists of individual II.3 at age 20 years. Flattening, underdevelopment, and squaring of the heads of the metacarpal bones, particularly at metacarpal IV bilaterally, are indicated (arrows). Also note bilateral clinodactyly as an incidental finding. B–E, Radiographs of individual II.9 at age 10 years. B, Standard radiograph of the pelvis. Flattening and irregular delineation of the left femoral epiphysis are indicated (arrow). Also note the broadening of the femoral neck, particularly at the left side. C, Standard radiograph of the hands and wrists. Subtle flattening and squaring of the metacarpal heads are indicated (arrows). D, Standard radiograph of the left knee and lower leg. Note slight overtubulation and narrowness of the diaphyses of the femur, tibia, and fibula. E, Detail of the left tibia and fibula. F, Standard radiograph of the pelvis of individual II.10 at age 7 years. Slight flattening and irregularity of the femoral epiphyses are indicated (arrows). Also note the broadening of the femoral neck, particularly at the left side (asterisk [*]). G, Spot view of the slightly flattened and irregular left femoral epiphysis of individual II.10.