Spondylocostal Dysostosis 6, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that spondylocostal dysostosis-6 (SCDO6) is caused by compound heterozygous mutation in the RIPPLY2 gene (609891) on chromosome 6q14. One such family has been reported.

For a general phenotypic description and a discussion of genetic heterogeneity of spondylocostal dysostosis, see SCDO1 (277300).

Clinical Features

McInerney-Leo et al. (2015) studied 2 brothers with segmentation defects of the vertebrae. The proband had failure of formation of the posterior elements of C1 to C4 with descent of the occipital bone, causing spinal canal stenosis and spinal cord compression. He also displayed hemivertebrae and butterfly vertebrae between T2 and T7, resulting in mild thoracic scoliosis. His brother had deficiency of the posterior elements of C1 to C3, left hemivertebrae at C4 and T9, and a right hemivertebra at T4, causing marked cervical kyphosis at the C2/C3 level with associated cord compression. Their nonconsanguineous parents, sister, and maternal grandfather and grandmother had normal spines by radiologic assessment.

Molecular Genetics

In 2 brothers with segmentation defects of the vertebrae, who had previously been tested negative for mutation in 4 genes known to be associated with autosomal recessive spondylocostal dysostosis, McInerney-Leo et al. (2015) performed whole-exome sequencing and identified compound heterozygosity for a nonsense mutation (R80X; 609891.0001) and a splice site mutation (c.240-4T-G; 609891.0002) in the RIPPLY2 gene that segregated with disease in the family. Analysis of the exome data for variation in 8 genes previously reported to be associated with SCDO or Klippel-Feil syndrome (see 118100) revealed no coding or splice site mutations, and no copy number variation affecting RIPPLY2 was detected. In vitro functional analysis demonstrated significantly reduced transcriptional repression activity with the R80X mutant compared to wildtype RIPPLY2. The authors stated that functional analysis of the splice site mutation could not be accomplished because of the location of the mutation and the likely restriction expression of RIPPLY2 to embryogenesis.