ESPE Abstracts

Background: Skeletal dysplasias (SD) are a heterogeneous group of heritable conditions with generalized bone and cartilage impairment caused by pathogenic variants in genes primarily affecting skeletogenesis and/or bone homeostasis. In this study, we conducted a next-generation sequencing (NGS) in patients with a suspected SD to reveal the underlying etiologies of skeletal dysplasia.

Methods: Thirty-four pediatric patients with skeletal dysplasia were subjected to targeted exome sequencing study or NGS-based gene panel sequencing.

Results: The clinical and genetic diagnoses were confirmed in 27 out of the 34 patients, and the diagnostic yield was 79.4%. At the time of diagnosis, the average age was 5.93±8.5 years and the average height SDS was -1.84±2.12. In these patients, 34 variants were identified, of which, 14 (41.1%) pathogenic or likely pathogenic variants were found in 12 genes (NPR2, GORAB, LMX1B, ALPL, NBAS, MATN3, SHOX, SMAD3, COL1A1, COL1A2, COL2A1, FKBP10), and 16 were novel variants. In patients with skeletal involvement and other clinical manifestations including dysmorphisms or multiple congenital anomalies, and developmental delay, the diagnosis rate was much higher (11 out of 12, 91.7%) than in those who had isolated skeletal involvement only (16 out of 22, 72.7%).

Conclusions: NGS-based approaches can be useful for diagnosing SD which has clinical and genetic heterogeneity. In particular, considering the high diagnosis rate of patients with skeletal dysplasia and accompanying abnormalities, active genetic evaluation is necessary for them.