title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
abstract: 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.
authors.affiliation: Department of Pediatrics, King Saud Medical Complex, Riyadh 11196, Saudi Arabia.
authors.forename: Maha
authors.initials: M
authors.lastname: Faden
authors.affiliation: Department of Genetics, King Faisal and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Fatema
authors.initials: F
authors.lastname: AlZahrani
authors.affiliation: 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.
authors.forename: Roberto
authors.initials: R
authors.lastname: Mendoza-Londono
authors.affiliation: 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.
authors.forename: Lucie
authors.initials: L
authors.lastname: Dupuis
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Taila
authors.initials: T
authors.lastname: Hartley
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Kannu
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada.
authors.forename: Julian A
authors.initials: JA
authors.lastname: Raiman
authors.affiliation: 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.
authors.forename: Andrew
authors.initials: A
authors.lastname: Howard
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Wen
authors.initials: W
authors.lastname: Qin
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC H3A 0G4, Canada; McGill University and Genome Quebec Innovation Center, Montreal, QC H3A 0G4, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Tetreault
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Joan Qiongchao
authors.initials: JQ
authors.lastname: Xi
authors.affiliation: Deparment of Radiology, King Saud Medical Complex, Riyadh 11196, Saudi Arabia.
authors.forename: Imadeddin
authors.initials: I
authors.lastname: Al-Thamer
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Maas
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Kym
authors.initials: K
authors.lastname: Boycott
authors.affiliation: 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: falkuraya@kfshrc.edu.sa.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000293:Adolescent; D000818:Animals; D001848:Bone Diseases, Developmental / Q000235:genetics* / Q000473:pathology; D002648:Child; D003241:Consanguinity; D015252:Deoxyribonucleases, Type II Site-Specific; D004392:Dwarfism / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D059472:Exome; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D051379:Mice; D009139:Musculoskeletal Abnormalities / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009999:Ossification, Heterotopic / Q000235:genetics*; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010521:Periosteum / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: C056130:endodeoxyribonuclease BspHI; D015252:Deoxyribonucleases, Type II Site-Specific
keywords: autozygome; craniosynostosis; exome; matchmaking; mucopolysaccharidosis; skeletal dysplasia