Abstract：
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 in 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 a de novo heterozygous variant of c.508C>T (p.R170W) of the TNNI3 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 a 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 by TNNI3 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.
CONCLUSIONS: Phenylalanine hydroxylase deficiency and RCM are rare diseases with complex clinical manifestations. The PAH: c.331C>T (p.R111X)/c.940C>A (p.P341T) and TNNI3: c.508C>T (p.R170W) variants probably underlay the RCM and PKU in this child.
METHODS: A child with RCM in conjunct with PKU who was admitted to the Children\'s Hospital Affiliated to Zhengzhou University in 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 a de novo heterozygous variant of c.508C>T (p.R170W) of the TNNI3 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 a 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 by TNNI3 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.
CONCLUSIONS: Phenylalanine hydroxylase deficiency and RCM are rare diseases with complex clinical manifestations. The PAH: c.331C>T (p.R111X)/c.940C>A (p.P341T) and TNNI3: c.508C>T (p.R170W) variants probably underlay the RCM and PKU in this child.
摘要：
目的：分析1例限制性心肌病（RCM）和苯丙酮尿症（PKU）患儿的临床和遗传特征，并通过文献综述总结儿童RCM的临床特点和遗传多样性。
方法：选择2020年6月郑州大学附属儿童医院因眼睑和下肢水肿1年，加重1个月以上的RCM合并PKU患儿作为研究对象。收集相关临床资料。收集儿童及其父母的外周血样本进行全外显子组测序(WES)。通过Sanger测序和生物信息学分析验证候选变体。童年,以TNNI3基因和限制性心肌病为关键词搜索万方数据知识服务平台,中国期刊全文数据库和PubMed数据库,搜索期限从成立之时到2022年8月。总结了TNNI3基因变异的临床表现和特点。
结果：孩子，一个2岁4个月大的男性,智力正常,面部特征和正常的头发和皮肤颜色，但是他的运动和身体发育被推迟了，此外伴有双侧眼睑及下肢水肿。WES和Sanger测序结果表明，他拥有PAH基因的复合杂合变体，即c.331C>T（p。R111X）和c.940C>A（p。P341T),从他的父亲和母亲那里继承下来，分别。此外,他还拥有c.508C>T的从头杂合变体（p。TNNI3基因的R170W)。根据美国医学遗传学和基因组学学院（ACMG）的指南，TNNI3：c.508C>T（p。R170W)被归类为致病变体(PS2+PS4+PM2_支持+PM5)，PAH：c.333C>T（p。R111X)作为致病变体(PVS1+PM2_支持+PM3+PP4)，和c.940C>A（p。P341T）作为可能的致病变体（PM2_支持PM3PM5PP4）。共检索到30名由TNNI3基因变异引起的RCM患儿，男女比例为1:1.55，表现包括心力衰竭，窦性心律,双心房扩大,ST-T波变化,心室限制性充盈，心室舒张功能下降。总共鉴定了16种TNI3基因变体，其中c.575G>A是最常见的，所有病例都符合常染色体显性遗传。
结论：苯丙氨酸羟化酶缺乏症和RCM是少见疾病，临床表现复杂。PAH：c.333C>T（p。R111X）/c.940C>A（p。P341T）和TNNI3：c.508C>T（p。R170W）变体可能是该孩子的RCM和PKU的基础。
方法：选择2020年6月郑州大学附属儿童医院因眼睑和下肢水肿1年，加重1个月以上的RCM合并PKU患儿作为研究对象。收集相关临床资料。收集儿童及其父母的外周血样本进行全外显子组测序(WES)。通过Sanger测序和生物信息学分析验证候选变体。童年,以TNNI3基因和限制性心肌病为关键词搜索万方数据知识服务平台,中国期刊全文数据库和PubMed数据库,搜索期限从成立之时到2022年8月。总结了TNNI3基因变异的临床表现和特点。
结果：孩子，一个2岁4个月大的男性,智力正常,面部特征和正常的头发和皮肤颜色，但是他的运动和身体发育被推迟了，此外伴有双侧眼睑及下肢水肿。WES和Sanger测序结果表明，他拥有PAH基因的复合杂合变体，即c.331C>T（p。R111X）和c.940C>A（p。P341T),从他的父亲和母亲那里继承下来，分别。此外,他还拥有c.508C>T的从头杂合变体（p。TNNI3基因的R170W)。根据美国医学遗传学和基因组学学院（ACMG）的指南，TNNI3：c.508C>T（p。R170W)被归类为致病变体(PS2+PS4+PM2_支持+PM5)，PAH：c.333C>T（p。R111X)作为致病变体(PVS1+PM2_支持+PM3+PP4)，和c.940C>A（p。P341T）作为可能的致病变体（PM2_支持PM3PM5PP4）。共检索到30名由TNNI3基因变异引起的RCM患儿，男女比例为1:1.55，表现包括心力衰竭，窦性心律,双心房扩大,ST-T波变化,心室限制性充盈，心室舒张功能下降。总共鉴定了16种TNI3基因变体，其中c.575G>A是最常见的，所有病例都符合常染色体显性遗传。
结论：苯丙氨酸羟化酶缺乏症和RCM是少见疾病，临床表现复杂。PAH：c.333C>T（p。R111X）/c.940C>A（p。P341T）和TNNI3：c.508C>T（p。R170W）变体可能是该孩子的RCM和PKU的基础。
