COG6基因复合杂合突变所致先天性糖基化障碍一例并文献复习

Congenital disorder of glycosylation caused by compound heterozygous mutation of the COG6 gene:a case report and literature review

目的分析COG6基因复合杂合突变所致先天性糖基化障碍(congenital disorder of glycosylation caused by compound heterozygous mutation of the COG6 gene,COG6-CDG)的临床表现和基因突变特点。方法回顾解放军总医院第七医学中心附属八一儿童医院2019年8月收治的1例COG6-CDG患儿的临床资料。以"先天性糖基化障碍ⅡL型、先天性糖基化缺陷ⅡL、COG6、COG6-CDG、congenital disorders of glycosylation typeⅡL、congenital disorders of glycosylationⅡL"为关键词,检索中国知网、万方数据库、维普数据库、Pubmed及Web of Science等数据库自建库以来至2020年7月收录的文献。总结COG6-CDG的临床特征及基因突变特点。结果(1)临床资料:患儿为男婴,胎龄27周+5,出生体重1180 g,生后59 d入院,主要表现多系统受累,包括不明原因进行性肝脾肿大伴黄疸、腹水,血小板持续低下,小头畸形、四肢张力低,皮肤少汗、角化过度,反复发热、感染、低血糖,合并心、胃肠道、肺、肾、眼底、凝血系统等功能异常。转入本院后予呼吸机辅助呼吸、抗感染、腹腔穿刺置管引流、输注血制品等积极对症支持治疗,患儿临床表现进行性加重,于生后192 d死于多器官功能衰竭。核心家系全外显子组检测发现COG6基因(NM_020751.2)存在复合杂合突变,外显子7存在c.662C>T(p.T221M)错义突变,来源于母亲;外显子5存在c.443T>C(p.I148T)错义突变,来源于父亲。这2个突变均未在人类基因突变库中收录,为未报道的新突变。(2)文献复习:共检索到8篇相关文献。文献报告的20例主要表现为不同程度的神经系统异常和生长发育迟缓,合并肝脏、心脏、胃肠道、血液、免疫、牙齿和骨骼等系统功能异常,且均有智力障碍和生长发育落后,9例至文献报道时已死亡。文献共报道了11个基因突变位点,深度内含子c.1167-24A>G的剪接突变最多(7例),其次分别是c.1646G>T(4例)和c.511C>T(3例)。结论COG6-CDG临床上主要表现为多系统、多器官功能障碍,总体临床预后不良,基因检测有助于明确诊断。本例的基因突变为c.662C>T(p.T221M)和c.443T>C(p.I148T)复合杂合突变,为未报道的新突变,拓宽了COG6基因的突变谱。

Objective To analyze the clinical and gene mutation characteristics of congenital disorder of glycosylation(CDG)caused by compound heterozygous mutation of the COG6 gene(COG6-CDG).Methods This study retrospectively analyzed the clinical data and genetic test results of a patient with COG6-CDG in Bayi Children's Hospital,the Seventh Affiliated Medical Center of Chinese PLA General Hospital,in August 2019.Literature was retrieved with keywords including COG6,COG6-CDG,congenital disorders of glycosylation typeⅡL and congenital disorders of glycosylationⅡL in China National Knowledge Infrastructure,Wanfang Database,VIP Database,PubMed,and Web of Science Database from the establishment to July 2020,to summarize the clinical and genetic characteristics of COG6-CDG.Results(1)Case report:The 59-day-old baby boy,with a gestational age of 27+5 weeks and birth weight of 1180 g,presented with multi-system involvement on admission,including unidentified progressive hepatosplenomegaly with jaundice and ascites,persistent thrombocytopenia,microcephaly,hypotonia,hypohidrosis,hyperkeratosis,and recurrent hyperthermia,infection,and hypoglycemia,as well as dysfunctions of the heart,gastrointestinal tract,lungs,kidneys,ocular fundus,and the coagulation system.Despite given ventilator-assisted ventilation,anti-infection therapy,abdominal puncture and drainage,and blood transfusion,the patient still had an aggravated condition and eventually died of multiple organ failures 192 d after birth.Genetic analysis showed that the nuclear family carried compound heterozygous mutations in the COG6 gene(NM_020751.2),including missense mutations of c.662C>T(p.T221M)in exon 7 and c.443T>C(p.I148T)in exon 5,which were both novel mutations and originated from the mother and father,respectively.(2)Literature review:Eight related papers were retrieved,including 20 cases.The main manifestations were various degrees of nervous system abnormalities and growth retardation,complicated by abnormalities of the liver,heart,gastrointestinal tract,blood,immunity,teeth,and bones.All the reported cases suffered from mental and growth retardation,and nine deaths were reported.A total of 11 COG6 gene mutations were identified,and most of them were c.1167-24A>G splicing mutations in a deep intron(seven cases),followed by c.1646G>T(four cases)and c.511C>T(three cases).Conclusions COG6-CDG commonly manifests as multi-system and multi-organ dysfunctions with poor prognosis.Gene detection is conducive to the accurate diagnosis of COG6-CDG.Our case carries compound heterozygous mutations of c.662C>T(p.T221M)and c.443T>C(p.I148T),which are unreported novel mutations.