Retrospective Analysis of Multi-Method Sequencing Results in Patients with Skeletal Dysplasia

Multi-Method Sequencing in Skeletal Dysplasia

Abstract

Objective: Skeletal dysplasia is a heterogeneous disease affecting the development of the skeletal system. Due to its complexity, clinical or radiological examinations can be informative; therefore, molecular approaches may be more effective for differential diagnosis and may assist in clarifying subtypes. Although studies in cohorts have identified associated genes and variants, further research is needed. This study aims to investigate the genotype-phenotype relationship in a Turkish cohort.

Methods: Thirty-six patients were involved in the study. Patients were classified according to the 2023 revision of the Nosology of Genetic Diseases of the Skeletal System. Following the genetic diagnostic algorithm, Sanger sequencing, targeted gene panels, clinical exome sequencing, or whole exome sequencing were performed. The existing literature was reviewed for some of the identified variants.

Results: The proportion of females (63.9%) was higher than that of males (36.1%). Notably, the parents of 16 patients (45.7%) were consanguineous. Pathogenic or likely pathogenic variants were identified in 29 of 36 patients, while variants of uncertain significance were identified in 6 patients. The diagnostic yield was 80% based on sequencing methods. The groups with the highest number of molecular diagnoses were group 2, type II collagen disorders (5 patients with COL2A1 variants), and group 34, syndromes with craniosynostosis (5 patients with FGFR2, FGFR3, TWIST1, or SMO variants), according to nosology.

Conclusion: This study emphasizes the genetic and phenotypic variation in skeletal dysplasia within a Turkish cohort. We expect these findings to contribute to the current literature and help clinicians in patient follow-up and assessment.