RESUMO
BACKGROUND: Hereditary multiple exostosis (HME) is an autosomal dominant skeletal disorder characterized by the development of multiple cartilage-covered tumors on the external surfaces of bones (osteochondromas). Most of HME cases result from heterozygous loss-of-function mutations in EXT1 or EXT2 gene. METHODS: Clinical examination was performed to diagnose the patients: Whole exome sequencing (WES) was used to identify pathogenic mutations in the proband, which is confirmed by Sanger sequencing and co-segregation analysis: qRT-PCR was performed to identify the mRNA expression level of EXT1 in patient peripheral blood samples: minigene splicing assay was performed to mimic the splicing process of EXT1 variants in vitro. RESULTS: We evaluated the pathogenicity of EXT1 c.1056 + 1G > T in a Chinese family with HME. The clinical, phenotypic, and genetic characterization of patients in this family were described. The variant was detected by whole-exome sequencing (WES) and confirmed by Sanger sequencing. Sequencing of the RT-PCR products from the patient's blood sample identified a large deletion (94 nucleotides), which is the whole exome 2 of the EXT1 cDNA. Splicing assay indicated that the mutated minigene produced alternatively spliced transcripts, which cause a frameshift resulting in an early termination of protein expression. CONCLUSIONS: Our study establishes the pathogenesis of the splicing mutation EXT1 c.1056 + 1G > T to HME and provides scientific foundation for accurate diagnosis and precise medical intervention for HME.