HIST1H1E基因突变致Rahman综合征1例并文献复习

Rahman syndrome caused by HIST1H1E gene mutation:a case report and literature review

目的探讨HIST1H1E基因突变致Rahman综合征的临床及遗传学特点。方法回顾性分析2018年6月收治的1例Rahman综合征患儿的临床资料。以Rahman综合征、HIST1H1E基因、组蛋白H1、突变、Rahman syndrome、HIST1H1E gene、Histone H1为检索词,检索建库至2019年12月中国知网、万方数据库、维普期刊服务平台及PubMed的相关文献进行文献复习。结果患儿,男,2岁8个月,身高98 cm、体质量19 kg、头围54 cm,面容特殊(脸颊丰满,发际线高,眦距增宽,眼睑裂狭窄),严重龋齿,隐睾。血氨基酸及肉碱谱检测示羟异戊酰肉碱增高,乙酰肉碱增高,鸟氨酸降低。骨龄相当于5.5岁。儿童发育筛查(DST)异常。全外显子组基因测序提示患儿HIST1H1E基因存在c.446dupA,p.Ser150Glufs*46杂合突变(新发变异),未在HGMD及gnomAD等数据库中收录,根据美国ACMG变异分类指南评级为致病性变异。检索到英文文献4篇,共31例Rahman综合征患儿,男13例、女18例;包括14种HIST1H1E基因突变型,均位于其C末端结构域94个碱基对的区域中,为移码突变,形成相同的具有38个氨基酸羧基末端的突变蛋白。结论HIST1H1E基因突变导致的Rahman综合征为罕见的常染色体显性遗传病,临床表现为轻度至重度智力障碍,发育落后和不同程度的躯体过度生长,全外显子基因检测可协助诊断。

Objective To analyze the clinical manifestations and genetic change of Rahman syndrome caused by HIST1H1E gene.Methods Clinical data of a patient with Rahman syndrome caused by HIST1H1E gene mutation in our hospital in October 2018 were retrospectively analyzed the and the related literature retrieved using"Rahman syndrome","HIST1H1E gene","histone H1"and"mutation"as the key words,in Chinese Knowledge Databases,Wanfang Data,Wiper Databases and PUBMED database before December 2019 were reviewed.Results A boy aged 2 years and 8 months old came to our hospital because of developmental retardation for more than 2 years.Physical examination found increased weight and large head circumference,high hairline,full cheeks,telecanthus,short palpebral fissures,scrotum without palpable testicles,but with firm mass in inguinal regions.Blood Amino acid and carnitine spectrum test showed a increase of hydroxyl isovalerate carnitine and acetyl carnitine,combining with a decrease of ornithine.Scrotum ultrasound revealed bilateral testis tissue in inguinal region.Bone age is consistent with the age of five and a half years.Echocardiographic and pituitary MRI showed normal.Child Developmental Screening Test with DQ<50 and MI<48.Whole exome sequencing identified a heterozygous mutation of c.446dupA(p.Ser150Glufs*46)on HIST1H1E gene.It's the first case with Rahman syndrome reported in china and this variant has not been reported in the Human Gene Mutation Database(HGMD)and gnomAD.Meanwhile this is a de novo frameshift mutation classified as pathogenic according to the American College of Medical Genetics and Genomics(ACMG).There are 31 cases(13 males and 18 females)with HIST1H1E gene mutation founded in four English publications.Fourteen mutations were included,all of which were frameshift mutation located in the 94 base pair region of C-terminal domain in HIST1H1E gene,which resulted in the formation of the same mutant protein with a 38-amino-acid tail.Conclusion Rahman syndrome is a rare autosomal dominant hereditary disease caused by HIST1H1E gene mutation,which is characterized by similar facial dysmorphism,combining with varied body overgrowth and intellectual disability.Whole exome sequencing may be helpful for early diagnosis.