Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations

Abstract

Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy. We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD. C21orf2 mutations have been recently found to cause isolated retinal degeneration and Jeune syndrome. We found a total of five biallelic C21orf2 mutations in six families out of nine: three missense and two splicing mutations in patients with various ethnic backgrounds. The pathogenic effects of the splicing (splice-site and branch-point) mutations were confirmed on RNA level, which showed complex patterns of abnormal splicing. C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora. Analysis of patients without C21orf2 mutation indicated genetic heterogeneity of axial SMD. Functional data in chondrocyte suggest C21orf2 is implicated in cartilage differentiation. C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function. Our study indicates that axial SMD is a member of a unique group of ciliopathy affecting skeleton and retina.

Novel Candidate Genes and a Wide Spectrum of Structural and Point Mutations Responsible for Inherited Retinal Dystrophies Revealed by Exome Sequencing

“…Patients in this family (A10) showed both RP and skeletal dysplasia, initially considered as unlinked traits. Again, our results prompted clinical re-evaluation, and supported C21orf2 association to this syndrome[26]. …”

Homozygous variant in C21orf2 in a case of Jeune syndrome with severe thoracic involvement: Extending the phenotypic spectrum

“…Consequently, C21orf2 was assessed in individuals with various ciliopathies; and homozygous and compound heterozygous mutations were identified in eight individuals with JATD from three families (Wheway et al, ). Recessive C21orf2 mutations were also identified in nine individuals from six different families with axial SMD (Wang et al, ).…”

“…It has been reported previously in nine homozygous and three compound heterozygous cases from four families of diverse ethnic backgrounds, and associated with variable phenotypes. Wang et al () reported homozygous mutations in four individuals from two families with axial SMD, all of whom had retinitis pigmentosa and short stature; three had hip dysplasia and two had a narrow thorax with short ribs. None had scoliosis.…”

“…The variant has been reported in ExAC (Exome Aggregation Consortium) (Lek et al, ) with MAF 0.0003; though no homozygotes have been reported in this control population. This particular variant in C21orf2 has been previously associated with disorders of ciliogenesis: Jeune syndrome (five homozygous cases in one family; two compound heterozygous cases in another family), axial SMD (four homozygous cases in two families) and isolated retinal dystrophy (one compound heterozygous case) (Wang et al, ; Wheway et al, ). Sanger sequencing confirmed the result.…”

“…Homozygous analysis revealed a mutation in C21orf2 a gene recently associated with skeletal ciliopathies (Wang et al, ; Wheway et al, ). Compound heterozygous analysis identified one candidate gene ( FBN3) .…”