ERF基因变异所致颅缝早闭患儿1例并文献复习

An infant with premature closure of cranial sutures due to variant of ERF gene and a literature review

目的分析1例颅缝早闭新生儿的临床信息与遗传学特征,明确该患儿颅缝早闭的临床表型及遗传学特征。方法选取2021年4月因"发现侧脑室增宽1个月余"收治于华中科技大学同济医学院附属武汉儿童医院的1例颅缝早闭患儿作为研究对象,并收集其临床信息。抽取患儿及其父母外周血样品,对患儿进行染色体核型分析,并进行全外显子组测序(WES)及家系Sanger测序验证。依据美国医学遗传学与基因组学学会(ACMG)变异解读标准与指南对基因变异进行致病性评估。文献检索以"ERF基因""颅缝早闭""ERF基因相关颅缝早闭""ERF mutation""craniosynostosis""ERF related craniosynostosis"等为关键词,设定检索年限建库至2021年12月,在美国医学文摘数据库(PubMed)、万方医学网及中国知网(CNKI)数据库中进行检索ERF基因所致颅缝早闭相关文献,并进行遗传学分析。结果患儿为1月16日龄女性,头颅X射线摄片检查结果示矢状缝早闭。WES结果提示患儿ERF基因存在变异c.787C>T(p.Q263*),父母未见该变异。根据ACMG变异标准与指南,变异判定为致病性变异(PVS1+PS2+PM2Supporting)。按文献检索策略共计检索到63例相关病例,共计64例患儿进行遗传学分析。绝大部分为散发病例,男性患儿居多;多颅缝累及(包括矢状缝、冠状缝、人字缝、额缝中的至少两条缝)占45.45%,单独矢状缝闭合占20.00%。主要临床表现包括眼距增宽、眼球突出、发育迟缓、颧骨发育不良等,部分患儿可能存在Chiari 1型畸形。目前研究结果显示ERF基因变异以剪切变异和缺失变异为主,且大部分先证者或先证者家系变异位点不同。结论ERF:c.787C>T(p.Q263*)可能为颅缝早闭患儿致病原因,该变异发现丰富了ERF的表型基因谱。

Objective To analyze the clinical and genetic characteristics of an infant with craniosynostosis.Methods An infant who was admitted to Wuhan Children′s Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology in April 2021 due to widening of the lateral ventricle for over a month was selected as the study subject.Clinical data of the patient was collected.Peripheral blood samples were collected from the infant and her parents for chromosomal karyotyping and whole exome sequencing.Candidate variant was verified by Sanger sequencing and bioinformatic analysis.Relevant literature was retrieved from the PubMed,Wanfang and CNKI databases(up to December 2021)by using key words includingERF gene,craniosynostosis,ERF mutation,craniosynostosis and ERF related craniosynostosis.Results The infant,a 1-month-and-16-day-old female,was found to have sagittal synostosis by cranial X-ray radiography.Genetic testing revealed that she has harbored a heterozygous c.787C>T(p.Q263*)variant of theERF gene,which was not found in either parent.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),the variant was predicted as pathogenic(PVS1+PS2+PM2_Supporting).In total 63 relevant cases were retrieved from the database,among which 64 were analyzed by genetic testing.Most of the cases were sporadic and were males.Multiple cranial sutures(including at least two of the sagittal suture,coronal suture,lambdoid suture,and frontal suture)were involved in 45.45%of the cases,and those with sagittal suture closure only have accounted for 20.00%.The main clinical manifestations have included hypertelorism,exophthalmos,development delay,malar dysplasia,etc.Chiari type 1 malformation may present in some patients.Variants of the ERF gene have mainly included splicing and deletional variants,and there was a strong genetic heterogeneity among the infants and their pedigrees.Conclusion The c.787C>T(p.Q263*)variant of theERF gene probably underlay the craniosynostosis of this infant.Above finding has enriched the phenotype-genotype spectrum of the ERF gene.