USP9X基因变异致限于女性型X-连锁综合征型智力障碍99型2例

Two cases of female-restricted X-linked syndromic mental retardation-99 caused by USP9X gene variations

目的总结分析USP9X基因变异致限于女性型X-连锁综合征型智力障碍99型(MRXS99F,OMIM:300968)的临床及基因型特点,提高临床医师对该病的认识。方法对2020年3月(例1)和2020年6月(例2)南京医科大学附属儿童医院收治的2例MRXS99F患儿的临床资料及基因型进行分析,并查阅国内外数据库相关文献,总结该病的临床特征及基因变异特点。结果2例患儿分别为6月龄(例1)及5岁(例2),均表现为神经运动发育迟缓。例1同时表现为身材矮小、皮肤色素分布不均、特殊面容、肌张力低下、反复呼吸道感染、喉软骨发育不良、房间隔缺损、喂养困难、听力异常及脑发育不良;例2脑电图异常。全外显子组测序技术检测显示,2例患儿分别携带USP9X基因变异:c.6972+1G>A和c.6437C>T,2种变异均未见于大型人群数据库及既往文献中报道,为罕见变异。全球共4篇文献报道了22例USP9X基因变异致MRXS99F病例,结合本研究共24例。既往22例患儿临床表现多特殊面容(20/22例);均有智力低下并运动和语言发育迟缓;22例基因变异类型均为新生变异。结论在国内首次报道该病的临床特点,USP9X基因功能缺失变异导致的MRXS99F主要表现为精神运动发育迟滞、语言障碍、特殊面容合及多种先天性畸形等,对于不明原因的发育迟缓、特殊面容且并多种先天畸形患儿,应尽早行高通量测序等遗传学检测明确病因。

Objective To summarize and analyze the clinical and genotype features of female-restricted X-linked syndromic mental retardation-99(MRXS99F,OMIM:300968)caused by USP9X gene mutation,and to improve the clinicians′understanding of the disease.Methods Clinical data and genotypes of 2 children with MRXS99F treated in the Children′s Hospital of Nanjing Medical University in March 2020(case 1)and June 2020(case 2)were analyzed,and the relevant databases at home and abroad were reviewed to summarize the clinical characteristics and gene variation characteristics of the disease.Results The 2 cases were 6 months old(case 1)and 5 years old(case 2),both showed psychomotor retardation.Case 1 presented a short stature,pigment abnormality,characteristic facial features,hypotonia,recurrent respiratory tract infections,laryngeal cartilage hypoplasia,atrial septal defect,feeding difficulty,hearing loss and brain hypoplasia.Case 2 had abnormal electroencephalogram.As confirmed by whole-exome sequencing,two children carried c.6972+1G>A,c.6437C>T of USP9X,respectively.Neither of the 2 variations was previously reported.Twenty-two cases of MRXS99F caused by USP9X gene mutation were reported in 4 literatures globally,and 24 cases were combined with this study.The clinical manifestations of 20/22 children had special faces.All of them accompanied mental retardation combined with motor and language retardation,and carried neonatal variation.Conclusions This is the first case report of MRXS99F induced by USP9X gene variation in China.MRXS99F caused by functional deletion and variation of USP9X gene is mainly characterized by psychomotor retardation,language disorder,special face and multiple congenital malformations.For children with unexplained growth retardation,special face and multiple congenital malformations,genetic testing like high-throughput sequencing should be carried out as early as possible to determine the etiology.