4. Discussion
Genetic investigations suggested that gene variations in the EXT1and EXT2 genes were often associated with HME, being responsible
for 70–95% of the cases. Mutations in EXT1 account for 56–78%
of HME cases, whereas mutations in EXT2 are detected in 21–44%
of cases (Jennes et al., 2009). The EXT1 gene mutation carriers
tend to show more severe symptoms of HME and a greater risk for
malignant transformation than the EXT2 gene mutation carriers did
(Francannet et al., 2001; Alvarez et al., 2007). The Human Gene Mutation
Database, (HGMD,http://www.hgmd.org) stored theEXT1 gene variants associated with HME that were published in the
peer-reviewed literature. To date, there are 592 gene mutation sites inEXT1 gene presented in (HGMD), which were categorized into 11
categories of mutation type, including frameshift mutation (44.3%),
nonsense mutation (21.6%), missense mutation (11.3%), Canonical-splice
mutation (9.8%), gross deletions/insertions/duplications
mutation (> 20 bp)
(account for 8.8%), noncoding
mutation (1.7%), inframe mutation
(1.5%), initiation mutation (0.3%), splice mutation (0.3%),
regulatory mutation (0.2%) and synonymous mutation (0.2%). In this
study, we identified a novel frameshift insertion mutation of exon 1 of
the EXT1 gene in a Chinese pedigree with HME. This gene variant
was not present in Clinvar/HGMD and current clinical reports.
Our result suggested that the novel frameshift insertion mutation of theEXT1 gene could cause the early termination of protein
translation (p.C109Lfs*80). Strong pathogenicity evidence (PVS1) shows
that this mutation could change gene open reading frame, resulting in
the loss of protein function; moderate pathogenicity evidence (PM2) of
this mutation was undetectable in Shenzhou genome database, Exome
Aggregation Consortium (ExAC), 1000 Genomes Project (1000GP) and HGMD;
and the pathogenic evidence (PP4) of the identified mutation was
consistent with the phenotype of HME. Generally, the combined evidences
(PVS1+ PM2+ PP4) supported that this novel mutation was pathogenic
(Ahmad et al.,2018; Biesecker et al.,2018; Rajarshi et al.,2018;) but
the origin of this pathogenic mutation is unknown.
In WES analysis on other family members, including
affected individuals
(Ⅱ-1, Ⅱ-5 and
Ⅲ-1) and unaffected individuals
(Ⅰ-2, Ⅱ-2, Ⅱ-3, Ⅱ-4, Ⅱ-6 and Ⅲ-2), we found that the identified mutation
of the proband (Ⅲ-3) was present in all the affected family members but
not present in the unaffected family members. Wu assumed that the
pathogenic mutation of the affected individuals (Ⅲ-1and Ⅲ-3) was
obtained from their fathers ((Ⅱ-1, Ⅱ-5), and the mutation of their
fathers inherited from the grandfather (Ⅰ-1) since the genetic type of
HME is autosomal dominant inheritance. Based on the current evidence,
the offspring of Ⅲ-1and Ⅲ-3 will carry this novel mutation with HME
incidence of 50% regardless of gender, while the offspring of the
unaffected member (Ⅲ-2) will not carry the HME-risk mutation.