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Mol Med Rep. 2017 Feb;15(2):657-664. doi: 10.3892/mmr.2016.6086. Epub 2016 Dec 29.

Identification of a novel mutation in the EXT1 gene from a patient with multiple osteochondromas by exome sequencing.

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Department of Laboratory Medicine, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China.
Department of Laboratory Medicine, The Fuzhou Second Affiliated Hospital of Xiamen University, Fuzhou, Fujian 350007, P.R. China.
Department of Bone Tumors, The Fuzhou Second Affiliated Hospital of Xiamen University, Fuzhou, Fujian 350007, P.R. China.
Medical College, Xiamen University, Xiamen, Fujian 361102, P.R. China.
Shenzhen Huada Gene Research Institute, Shenzhen, Fujian 518083, P.R. China.


Multiple osteochondromas (MO) is an autosomal skeletal disease with an elusive molecular mechanism. To further elucidate the genetic mechanism of the disease a three‑generation Chinese family with MO was observed and researched, and a novel frameshift mutation (c.335_336insA) in the exotosin 1 (EXT1) gene of one patient with MO was observed through exome sequencing. This was further validated by Sanger sequencing and comparison with 200 unrelated healthy controls. Immunohistochemistry and multiple sequence alignment were performed to determine the pathogenicity of the candidate mutation. Multiple sequence alignment suggested that codon 335 and 336 in the EXT1 gene were highly conserved regions in vertebrates. Immunohistochemistry revealed that EXT1 protein expression levels were decreased in a patient with MO and this mutation compared with a patient with MO who had no EXT1 mutation. Owing to the appearance of c.335_336insA in exon 1 of EXT1, a premature stop codon was introduced, resulting in truncated EXT1. As a result integrated and functional EXT1 was reduced. EXT1 is involved in the biosynthesis of heparan sulfate (HS), an essential molecule, and its dysfunction may lead to MO. The novel mutation of c.335_336insA in the EXT1 gene reported in the present study has enlarged the causal mutation spectrum of MO, and may assist genetic counseling and prenatal diagnosis of MO.

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