Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations

Am J Hum Genet. 2015 Oct 1;97(4):608-15. doi: 10.1016/j.ajhg.2015.08.007. Epub 2015 Sep 10.


Skeletal dysplasias are highly variable Mendelian phenotypes. Molecular diagnosis of skeletal dysplasias is complicated by their extreme clinical and genetic heterogeneity. We describe a clinically recognizable autosomal-recessive disorder in four affected siblings from a consanguineous Saudi family, comprising progressive spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, short fourth metatarsals, and intellectual disability. Combined autozygome/exome analysis identified a homozygous frameshift mutation in RSPRY1 with resulting nonsense-mediated decay. Using a gene-centric "matchmaking" system, we were able to identify a Peruvian simplex case subject whose phenotype is strikingly similar to the original Saudi family and whose exome sequencing had revealed a likely pathogenic homozygous missense variant in the same gene. RSPRY1 encodes a hypothetical RING and SPRY domain-containing protein of unknown physiological function. However, we detect strong RSPRY1 protein localization in murine embryonic osteoblasts and periosteal cells during primary endochondral ossification, consistent with a role in bone development. This study highlights the role of gene-centric matchmaking tools to establish causal links to genes, especially for rare or previously undescribed clinical entities.

Keywords: autozygome; craniosynostosis; exome; matchmaking; mucopolysaccharidosis; skeletal dysplasia.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Bone Diseases, Developmental / genetics*
  • Bone Diseases, Developmental / pathology
  • Child
  • Consanguinity
  • Deoxyribonucleases, Type II Site-Specific
  • Dwarfism / genetics
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism
  • Exome
  • Female
  • Genes, Recessive / genetics*
  • Homozygote
  • Humans
  • Intellectual Disability / genetics
  • Male
  • Mice
  • Musculoskeletal Abnormalities / genetics*
  • Musculoskeletal Abnormalities / pathology
  • Mutation / genetics*
  • Ossification, Heterotopic / genetics*
  • Osteoblasts / metabolism
  • Osteoblasts / pathology
  • Osteochondrodysplasias / genetics*
  • Osteochondrodysplasias / pathology
  • Pedigree
  • Periosteum / metabolism
  • Periosteum / pathology
  • Phenotype
  • Sequence Analysis, DNA


  • endodeoxyribonuclease BspHI
  • Deoxyribonucleases, Type II Site-Specific