Autosomal recessive Stickler syndrome resulting from a COL9A3 mutation

Abstract

Stickler syndrome is a connective tissue disorder characterized by hearing loss, ocular anomalies, palatal defects, and skeletal abnormalities. The autosomal dominant form is the most common, but autosomal recessive forms have also been described. We report the second case of autosomal recessive Stickler syndrome due to homozygosity for a loss of function mutation in COL9A3, which encodes the α3 chain of type IX procollagen. The clinical features were similar to the previously described COL9A3 Stickler syndrome family, including moderate to severe sensorineural hearing loss, high myopia, and both tibial and femoral bowing at birth. Radiographs demonstrated abnormal capital femoral epiphyses and mild irregularities of the vertebral endplates. This case further establishes the phenotype associated with mutations in this gene. We suggest that loss of the α3 chain of type IX collagen results in a Stickler syndrome phenotype similar to that of the other autosomal recessive forms caused by mutations in genes encoding the α1 and α2 chains of type IX collagen.

Homozygous Type IX collagen variants (COL9A1, COL9A2, and COL9A3) causing recessive Stickler syndrome—Expanding the phenotype

“…We report six patients from four pedigrees, with three novel variants causing recessive SS, in all cases from consanguineous parents. Our findings largely confirm the findings in previously described cases of recessive SS due to variants in the genes for Type IX collagen, COL9A1 , COL9A2 , and COL9A3 (Baker et al, ; Faletra et al, ; Hanson‐Kahn et al, ; Nikopoulos et al, ; Van Camp et al, ). Sensorineural hearing loss (SNHL) and high myopia are consistent features observed across all these patients.…”

“…While the vast majority of cases of SS are inherited in an autosomal dominant fashion, there are six families reported with features of SS associated with homozygous variants in genes for Type IX collagen, COL9A1, COL9A2 , and COL9A3 (see Table ) (Baker et al, ; Faletra et al, ; Hanson‐Kahn et al, ; Nikopoulos et al, ; Van Camp et al, ). These patients had high myopia, hypoplastic vitreous and sensorineural hearing loss, some evidence of joint dysplasia, and facial flattening but no palate abnormalities.…”

Stickler Syndrome: A Review of Clinical Manifestations and the Genetics Evaluation

“…This is because, while COL11A2 is expressed in the joints, inner ear, and craniofacial structures, it is not expressed in the eye [ 14 ]. More rare than the AD forms, biallelic pathogenic variants in COL9A1 , COL9A2 , and COL9A3 have been reported to cause recessive forms of Stickler Syndrome (Stickler Syndromes 4-6 [STL4-6]) [ 9 , 10 , 11 , 23 ]. Biallelic variant in COL11A1 have also been reported in cases of AR SS, although typically are associated with a more severe skeletal dysplasia [ 24 ].…”

The α2 chain of type IX collagen is essential for type IX collagen biosynthesis

“…About 80–90% of cases result from dominant mutations in the type II procollagen gene ( COL2A1 , OMIM: 120140; STL1, OMIM: 108300, 609,508) and most of the remaining cases result from dominant type XI procollagen gene ( COL11A1 , OMIM: 120280 [STL2, OMIM: 604841]; COL11A2 , OMIM: 120290 [STL3, OMIM: 184840]) mutations. Six families with autosomal recessive Stickler syndrome due to mutations in COL9A1 , OMIM: 120210 (STL4, OMIM: 614134), COL9A2 , OMIM: 120260 (STL5, OMIM: 614284), or COL9A3 , OMIM: 120270 (STL6), which together encode type IX procollagen, have been described (Hanson‐Kahn et al, ; Robin et al, ).…”

“…We can further infer that Stickler syndrome resulting from homozygosity for a loss‐of‐function mutation in COL9A2 is mechanistically similar to the consequences of loss of the COL9A1 gene product (Baker et al, ). As recessively inherited loss of function mutations in COL9A3 also result in Stickler syndrome in humans (Faletra et al, ; Hanson‐Kahn et al, ), it seems likely that the loss of α3(IX) would also result in functional knockout of type IX collagen.…”