Expanding the phenome and variome of skeletal dysplasia

Genet Med. 2018 Dec;20(12):1609-1616. doi: 10.1038/gim.2018.50. Epub 2018 Apr 5.


Purpose: To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized.

Methods: Detailed phenotyping and next-generation sequencing (panel and exome).

Results: Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average.

Conclusion: By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.

Keywords: Toriello–Carey; craniosynostosis; osteogenesis imperfecta.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Blood Proteins / genetics
  • Carboxylic Ester Hydrolases
  • Cohort Studies
  • Exome / genetics*
  • Exoribonucleases / genetics
  • Female
  • Fetal Proteins / genetics
  • Founder Effect
  • Genetic Heterogeneity*
  • Genetic Predisposition to Disease*
  • Genetics, Population
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Male
  • Membrane Proteins / genetics
  • Musculoskeletal Abnormalities / classification
  • Musculoskeletal Abnormalities / genetics*
  • Musculoskeletal Abnormalities / pathology
  • Neoplasm Proteins / genetics
  • Oncogene Proteins / genetics
  • Phenotype
  • Receptors, Cell Surface / genetics
  • Wnt3A Protein / genetics


  • Blood Proteins
  • DIP2C protein, human
  • Fetal Proteins
  • Intracellular Signaling Peptides and Proteins
  • LINC01565 protein, human
  • Membrane Proteins
  • Neoplasm Proteins
  • Oncogene Proteins
  • RIN1 protein, human
  • Receptors, Cell Surface
  • SUCO protein, human
  • WNT3A protein, human
  • Wnt3A Protein
  • Exoribonucleases
  • Carboxylic Ester Hydrolases
  • PGAP3 protein, human
  • PAN2 protein, human