BMPER mutation in diaphanospondylodysostosis identified by ancestral autozygosity mapping and targeted high-throughput sequencing

Diaphanospondylodysostosis (DSD) is a rare, recessively inherited, perinatal lethal skeletal disorder. The low frequency and perinatal lethality of DSD makes assembling a large set of families for traditional linkage-based genetic approaches challenging. By searching for evidence of unknown ancestral consanguinity, we identified two autozygous intervals, comprising 34 Mbps, unique to a single case of DSD. Empirically testing for ancestral consanguinity was effective in localizing the causative variant, thereby reducing the genomic space within which the mutation resides. High-throughput sequence analysis of exons captured from these intervals demonstrated that the affected individual was homozygous for a null mutation in BMPER, which encodes the bone morphogenetic protein-binding endothelial cell precursor-derived regulator. Mutations in BMPER were subsequently found in three additional DSD cases, confirming that defects in BMPER produce DSD. Phenotypic similarities between DSD and Bmper null mice indicate that BMPER-mediated signaling plays an essential role in vertebral segmentation early in human development.