关键词: HUWE1基因, 全外显子组测序, 错义变异, X连锁智力障碍, 临床表型

Abstract:

Objective To analyze the clinical manifestations and genetic characteristics of X-linked intellectual disability（XLID） with HUWE1 mutation. Methods The clinical data and laboratory determination results of a boy with XLID were collected. The gene mutation of the patient with XLID and his parents was detected by whole-exome sequencing and verified by Sanger sequencing. Bioinformatic analysis of the mutation was performed to determine the pathogenicity. The clinical and gene mutation characteristics of XLID were summarized by a literature review. Results The patient with XLID showed intellectual disability，motor developmental delay，speech delay，short stature and facial dysmorphism. The whole-exome sequencing identified a de novo hemizygous mutation c.12227C>G（p.Pro4076Arg） in HUWE1 gene of the patient. Sanger sequencing showed that the mutation existed and his parents did not have the mutation. This mutation was not included by searching ESP database，1000 Genomes database，ExAC database and gnomAD database. The mutation c.12227C>G（p.Pro4076Arg）in HUWE1 gene reduced the flexibility of HECT domain. The results of literature review showed that 51 patients with XLID caused by HUWE1 mutation were mainly characterized by moderate to severe intellectual disability（92%），motor developmental delay（92%），speech delay（83%）and short stature（78%）. There were 27 mutations consisting of 25 missense mutations and 2 frame shift mutations. The 11 mutations （involved in 21 patients）located in HECT domain were characterized by moderate to severe intellectual disability（100%）and typical facial dysmorphism consisting of deep set eyes（93%），blepharophimosis（93%） and epicanthus（85%）. Conclusions Patients with HUWE1 mutation located in HECT domain have a severe phenotype and recognizable facial features. XLID should be considered in patients with clinical manifestations of intellectual disability，short stature and facial dysmorphism. A genetic analysis is helpful in arriving at a definite diagnosis.

Key words: HUWE1 gene, Whole-exome sequencing, Missense mutation, X-linked intellectual disability, Clinical manifestation