Discussion
In
the present study, we used whole-exome sequencing to identify a novel
UBE2A splice site mutation (c.241+1
G>A) in a Chinese proband with an X-linked Intellectual
Disability. According to recent
reports, this is the second case report of this syndrome with a novel
splice site mutation in China.
Notably, we report novel molecular
and clinical data of this patient with intellectual
disability.
Thus far, only two splice-site mutations in UBE2A, seven missense
mutations in UBE2A, and four larger deletions in UBE2A have been
reported [7, 12, 15-23].
Besides,
all probands with UBE2A deficiency syndrome have resemblance phenotypes,
including characteristic facial appearance, speech anomalies, and
intellectual disability [20, 24]. However, our proband found novel
clinical appearance, including a typical four-finger line and erected
head unstable, which has not been described in previous patients.
In
addition,
the
phenotypes of all reported proband with UBE2A mutational syndrome and a
patient described in the present study were analyzed, three groups of
UBE2A mutational syndrome could be classified: (1) the group of those
with larger deletions (largedel), (2) the group of those with missense
mutation (miss) and (3) the group of those with splice site mutation
(splice) (Table 1).
All
patients were male and showed severe intellectual disability and speech
impairment.
Interestingly, the boys with splice site mutation had a significantly
higher erected head unstable (EHU) (1/1),
white matter abnormalities (WMA)
(2/2), wide face (WF) (4/4) and
small penis (SP) (2/2), compared to boys with a missense mutation (0/0
EHU, 3/6 WMA, 3/7 WF, 8/12 SP) or larger deletions (0/0 EHU, 6/7 WMA,
0/0 WF, 7/9 SP). Furthermore, these results confirmed that splice site
mutation of UBE2A significantly decreased the risk of synophrys (2/4),
Heart defects (HD) (0/2) , Upslanting palpebral fissures (UPF) (0/4),
compared with a missense mutation of UBE2A (12/13 synophrys, 3/4 HD, 3/8
UPF) or larger deletions of UBE2A
(6/9
synophrys, 9/9 HD, 7/9 UPF) [7, 11, 18, 19, 22,
25].
According
to recent reports, four patients have not been reported with upslanting
palpebral fissures. Although these
analyses were based on a small statistically significant number of
patients that could not get a valid conclusion, it is also worth noting
this observation suggested that UBE2A splice site mutation might not be
at improved risk for upslanting palpebral fissures and heart defects.
Conversely, UBE2A splice site mutation might be at improved risk for
wide face, white matter abnormalities and small penis.
In conclusion, this report has demonstrated a novel splice site mutation
(c.241+1 G>A) in UBE2A gene resulting in an aberrant
appearance and severe intellectual disability in a Chinese proband.
The
patient was found novel clinical appearances, including a typical
four-finger line and erected head unstable. Together, our report expands
the mutation spectrum and clinical characteristics of UBE2A deficiency
syndrome (also called XLID) and may provide clinical evidence into
genetic diagnosis.