1. Introduction
Hereditary Multiple Exostoses
(HME) is a rare orphan autosomal-dominant pediatric disorder with a
prevalence of about 1:50 000 (Wicklund
et al., 1995; Schmale et al.,
1994). The disease is estimated to occur more frequently in males
(male-to-female ratio,1.5:1) (D’Arienzo et al., 2019). HME is
characterized by the formation of osteochondromas (non-malignant
cartilage-capped bony tumors) or exostoses within the perichondrium next
to the growth plates of long bones, ribs, hip and vertebrae in very
young and adolescent patients (Ryckx et al., 2013). Osteochondromas can
turn into chondrosarcomas or osteosarcomas that can be life threatening
in about 2% of the patients (Porter DE and Simpson AHRW,1999; Porter et
al., 2004). The current clinical treatment of HME is commonly to resect
the symptomatic chondrosarcomas or osteochondromas and to ameliorate the
associated skeletal defects. The etiological treatment is not yet
available as the evidence on etiological diagnosis of HME is limited.
The identification of likely pathogenic genes associated with HME was
reported in the past. Wu et al. reported that the majority of the
studied patients carried mutations in the exostosin-1 (EXT1 ) and
exostosin-2 (EXT2 ) genes (Wu et al., 1994; Wuyts et al., 1996).EXT1 consists of 11 exons and spans about 312kb at 8q24 (Ludecke
et al.,1997), while EXT2 comprises 16 exons and is located at
11p11.2, spanning about 150kb (Clines et al.,1997). It is known that the
genes belong to the EXT multigene family, are ubiquitously
expressed and act as tumor suppressors. The proteins encoded byEXT family genes are involved in the adhesion and/or
polymerization of heparin sulfate (HS) chains at HS proteoglycans
(HSPG’s) (Lind et al.,1998; McCormick et al., 1998; Busse et al.,2007).
To date, over 650 mutations in EXT1 and EXT2 have been
reported, most of which are nonsense, frameshift, or splice site,
resulting in the synthesis of truncated EXT proteins with no suppression
activity (Jennes et al., 2009; Ciavarella et al., 2013).
In this study, we identified a novel
frameshift insertion mutation in
the proband, which is absent both in Clinvar or Human Genome database
and current clinical reports. The novel frameshift insertion mutation
found in the proband was also confirmed in the affected individuals but
not in the unaffected individuals; Further, the Polyphen and SIFT
analysis were used to evaluate the effect of the frameshift insertion
mutation, with a support result of obtaining a dysfunctional protein
from the mutated gene. Therefore, we concluded that the genetic
variation caused by the frameshift insertion mutation could be
associated with the pathogenicity of HME in this pedigree. The finding
could be used as a new support on prenatal diagnosis for preventing the
birth defect incidence of HME.