Molecular diagnosis in a cohort of 114 patients with rare skeletal dysplasias

Abstract Molecular diagnosis is important to provide accurate genetic counseling of skeletal dysplasias (SD). Although next‐generation sequencing (NGS) techniques are currently the preferred methods for analyzing these conditions, some of the published results have not shown a detection rate as high as it would be expected. The present study aimed to assess the diagnostic yield of targeted NGS combined with Sanger sequencing (SS) for low‐coverage exons of genes of interest and exome sequencing (ES) in a series of patients with rare SD and use two patients as an example of our strategy. This study used two different in‐house panels. Of 93 variants found in 88/114 (77%) patients, 57 are novel. The pathogenic variants found in the following genes: B3GALT6 , PCYT1A , INPPL1 , LIFR , of four patients were only detected by SS. In conclusion, the high diagnostic yield reached in the present study can be attributed to both a good selection of patients and the utilization of the SS for the insufficiently covered regions. Additionally, the two case reports—a patient with acrodysostosis related to PRKAR1A and another with ciliopathy associated with KIAA0753 , add new and relevant clinical information to the current knowledge.