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.
- 1. Department of Pediatrics, King Saud Medical Complex, Riyadh 11196, Saudi Arabia.
- 2. Department of Genetics, King Faisal and Research Center, Riyadh 11211, Saudi Arabia.
- 3. Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada; The Bone Health Centre, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada.
- 4. Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
- 5. Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada.
- 6. The Bone Health Centre, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada; Division of Orthopedic Surgery, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada.
- 7. Department of Human Genetics, McGill University, Montreal, QC H3A 0G4, Canada; McGill University and Genome Quebec Innovation Center, Montreal, QC H3A 0G4, Canada.
- 8. Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
- 9. Deparment of Radiology, King Saud Medical Complex, Riyadh 11196, Saudi Arabia.
- 10. Department of Genetics, King Faisal and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia. Electronic address: [email protected].
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.