Expanding the phenome and variome of skeletal dysplasia

Purpose: To explain our knowledge about a sizable cohort (411 patients from 288 families) of numerous types of skeletal dysplasia who have been molecularly characterised.

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

Results: Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) which are novel) in 123 genes with established or tentative links to skeletal dysplasia. Additionally, we advise 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we observe that our cohort spans 36 established phenotypic groups through the Worldwide Skeletal Dysplasia Nosology, in addition to 18 novel skeletal dysplasia phenotypes that may ‘t be classified under these groups, e.g., the novel C3orf17-related skeletal dysplasia. We describe novel phenotypic facets of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a powerful founder effect for a lot of genes within our cohort, which permitted us to calculate the absolute minimum disease burden for that autosomal recessive types of skeletal dysplasia within our population (7.16E-04), that is much greater compared to global average.

Conclusion: By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, hopefully our study will enhance the diagnostic rate of patients using these conditions.