Investigation of uncharacterized spondylocostal dysostosis using whole exome sequencing

Skeletal dysplasias and dysostoses are a genotypically and phenotypically diverse group of disorders that affect the growth, development and maintenance of cartilage and bone. General disorders of bone affecting bones and cartilage throughout the body have been referred to as skeletal dysplasias, whereas defects that selectively affect certain bones or bone groups are called skeletal dysostoses. Despite this distinction, modern molecular techniques are showing that this division is somewhat superficial, given the similarity in their underlying causes. Although the rate of disease gene discovery has grown substantially since the advent of next-generation sequencing technologies, most of the disorders have unknown molecular defects. Skeletal dysostoses are rarely observed, occurring at such low incidence levels that no comprehensive study has ascertained their frequency. The effects range from mild growth inhibition to complete absence of entire bone groups. The axial skeleton is most often involved in skeletal dysostoses with common symptoms including poorly formed cranial bones, mandible, ribs and vertebrae. Several important signaling pathways control the migration and formation of mesodermal cells, which eventually differentiate into many elements of the vertebral column. The importance of these pathways, namely the T-box transcription factors, Wnt, Notch, and Smad pathways are integrally involved in the very early stages of vertebral development. Currently, the most cost-effective method of pathogenic gene discovery for rare genetic diseases is exome sequencing. Utilizing this technology, as well as SNP arrays for identity-by-descent loci mapping, two independent skeletal dysostosis cases with similar phenotypes were studied to determine pathogenic candidate genes. Next-generation sequencing and identity-by-descent analysis revealed a possible candidate gene, PM20D2, in one proband. The gene includes peptidase dimerization, peptidase M20/M25/M40, and N-myristolylation domains based on predicted functional analysis. It is implicated in various metabolic activities, having hydrolase, protein binding, and metallopeptidase molecular functions. Further investigation into this gene, as well as further studies of these probands is needed to understand the role, if any, the defect plays in the disease