Genome-wide chromatin binding of ZNF528-WT and ZNF528-c.1282C>T in Saos-2 cells.

We studied a family with severe primary osteoporosis carrying a heterozygous p.Arg8Phefs*14 deletion in COL1A2 leading to haploinsufficiency. Three affected individuals carried the mutation and presented nearly identical spinal fractures, but lacked other typical features of either osteogenesis imperfecta or Ehlers-Danlos syndrome. Although mutations leading to haploinsufficiency in COL1A2 are rare, mutations in COL1A1 that lead to less protein typically result in a milder phenotype. We hypothesized that other genetic factors may contribute to the severe phenotype in this family. We performed whole exome sequencing in five family members and identified in all three affected individuals a rare nonsense variant (c.1282C>T/p.Arg428*, rs150257846) in ZNF528. ChIP sequencing analyses on ZNF528 and ZNF528-c.1282C>T indicated that ZNF528 binding sites are linked to pathways and genes regulating bone morphology.