限制型心肌病合并苯丙酮尿症患儿1例的遗传学分析及文献回顾

Genetic analysis of a child with restricted cardiomyopathy and phenylketonuria and a literature review

目的分析1例罕见的儿童限制型心肌病合并苯丙酮尿症(PKU)患儿的临床及基因变异,通过文献回顾总结儿童限制型心肌病的临床特点及遗传学分析。方法选取2020年6月因"双眼睑及双下肢水肿1年,加重1月余"就诊于郑州大学附属儿童医院的1例限制型心肌病合并PKU患儿作为研究对象,并收集其临床相关资料。采集患儿及父母外周血样,进行全外显子组测序(WES)确定候选位点,Sanger测序进行验证确定变异位点,生物信息学软件分析变异致病性。以"儿童期发病""TNNI3基因""限制型心肌病"为关键词,在万方数据知识服务平台、中国期刊全文数据库中设定检索年限为建库至2022年8月检索中文文献。并以"childhood""TNNI3 gene""restrictive cardiomyopathy"为关键词在生物医学文献数据库(PubMed)中设定检索年限为建库至2022年8月搜索外文文献,总结其临床表现和TNNI3基因变异特点。结果患儿为2岁4月龄男性,智力正常,运动、体格发育落后,未见特殊面容,头发和皮肤色泽未见明显异常,双眼睑及下肢浮肿。WES及Sanger测序结果提示患儿PAH基因存在父源的c.331C>T(p.R111X)和母源的c.940C>A(p.P341T)复合杂合变异。同时患儿TNNI3基因存在新发杂合变异c.508C>T(p.R170W),父亲和母亲未见该变异。依据美国医学遗传学与基因组学学会变异评级相关指南,TNNI3:c.508C>T(p.R170W)评级为致病性变异(PS2+PS4+PM2Supporting+PM5),PAH:c.331C>T(p.R111X)评级为致病性变异(PVS1+PM2Supporting+PM3+PP4),c.940C>A(p.P341T)评级为可能致病性变异(PM2Supporting+PM3+PM5+PP4)。按检索限定共检索到TNNI3基因变异所致儿童期发病的限制型心肌病30例,男女比例约1:1.55,表现为心力衰竭、窦性心律、双心房增大、ST-T波改变、心室限制型充盈、心室舒张功能下降等。30例共发现TNNI3基因16种不同变异位点,其中c.575G>A最常见,均符合常染色体显性遗传方式。结论苯丙氨酸羟化酶缺乏症与限制性心肌病均为罕见病,临床表现复杂。基因检测技术发现该患儿存在PAH:c.331C>T(p.R111X)/c.940C>A(p.P341T)复合杂合变异及TNNI3:c.508C>T(p.R170W)变异,考虑是共患限制型心肌病及PKU的原因。

Objective To analyze the clinical and genetic characteristics of a child with restricted cardiomyopathy(RCM)and phenylketonuria(PKU),and summarize the clinical characteristics and genetic diversity of RCM in children through a literature review.Methods A child with RCM in conjunct with PKU who was admitted to the Children′s Hospital Affiliated to Zhengzhou University on June 2020 due to edema of eyelids and lower limbs for 1 year and aggravation for over 1 month was selected as the study subject.Relevant clinical data were collected.Peripheral blood samples of the child and his parents were collected for whole exome sequencing(WES).Candidate variants were validated by Sanger sequencing and bioinformatic analysis.Childhood,TNNI3 gene and restricted cardiomyopathy were used as the keywords to search the Wanfang data knowledge service platform,Chinese Journal Full-text database and PubMed database,and the search period was limited to from the time of establishment till August 2022.Clinical manifestations and characteristics of the TNNI3 gene variants were summarized.Results The child,a 2-year-old-and-4-month-old male,had normal intelligence,facial features and normal hair and skin color,but his motor and physical development was delayed,in addition with edema of bilateral eyelids and lower limbs.The results of WES and Sanger sequencing revealed that he has harbored compound heterozygous variants of the PAH gene,namely c.331C>T(p.R111X)and c.940C>A(p.P341T),which were inherited from his father and mother,respectively.In addition,he has also harbored ade novo heterozygous variant of c.508C>T(p.R170W)of theTNNI3 gene.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),the TNNI3:c.508C>T(p.R170W)was classified as a pathogenic variant(PS2+PS4+PM2_Supporting+PM5),PAH:c.331C>T(p.R111X)as pathogenic variant(PVS1+PM2_Supporting+PM3+PP4),and c.940C>A(p.P341T)as a likely pathogenic variant(PM2_Supporting+PM3+PM5+PP4).In total 30 children with RCM caused byTNNI3 gene variants were retrieved,with a male-to-female ratio of 1:1.55 and manifestations including heart failure,sinus rhythm,bi-atrial enlargement,ST-T wave change,ventricular restricted filling,and decreased ventricular diastolic function.In total 16 variants of the TNNI3 gene were identified,among which c.575G>A was the most common,and all cases had conformed to an autosomal dominant inheritance.Conclusion Phenylalanine hydroxylase deficiency and RCM are rare diseases with complex clinical manifestations.PAH:c.331C>T(p.R111X)/c.940C>A(p.P341T)andTNNI3:c.508C>T(p.R170W)variants probably underlay the RCM and PKU in this child.