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.