Abstract: Objective　To explore the clinical characteristics, diagnosis and treatment of congenital disorder of glycosylation type Ⅳ (CDG-Ⅳ) caused by NGLY1 gene mutation. Method　The clinical data and gene test results of two sisters with CDG-Ⅳ in the same family were reviewed, and the literatures were reviewed. Results　The proband was an 8-month-old girl whose clinical manifestations were psychomotor retardation, hypohidrosis, less tear, poor catacleisis, small hands and feet, and so on. Prenatal screening for Down syndrome at 6 months of gestational age indicated high risk, and no abnormalities were found in amniocentesis. Fetal ultrasonography indicated intrauterine growth retardation. The proband had a 4-year-old sister, and their clinical manifestations and growth history were similar. Their parents were not consanguineous, and the phenotype was normal. The karyotype analysis and chromosome microdeletion analysis of the proband were normal. NGLY1 gene mutation was found in proband and all other members of the family by whole exon gene sequencing. The proband’s elder sister had the same NGLY1 gene mutation originating from the father’s frameshift mutation (which could cause changes in the amino acid p.S546Ffs*12) and the mother's point mutation. NGLY1 gene has been reported to be associated with CDG-Ⅳin foreign literatures. The same NGLY1 gene mutation (point mutation at 1003+3 site and frameshift mutation at 1637 site) was not retrieved in current China National Knowledge Infrastructure (CNKI), Wanfang, PubMed and Clinvar databases, suggesting that it may be a new mutation. Conclusion　In this case, the proband and her elder sister's NGLY1 gene mutations were derived from their parents. The NGLY1 gene mutation can cause CDG-Ⅳ, and its clinical phenotype is consistent with the literature.