Analysis ofPKP2 gene variants in a child with Arrhythmogenic right ventricular cardiomyopathy
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目的 探讨1例致心律失常性右室心肌病(ARVC)患儿的临床特征与遗传学病因。 方法 选取2022年8月23日于福建省儿童医院就诊的1例ARVC患儿作为研究对象。采集患儿的相关临床资料，抽取患儿及其父母的外周静脉血样，应用全外显子组测序(WES)对患儿进行基因检测，采用Sanger测序进行家系验证，并对候选变异进行致病性分析。 结果 本研究患儿为6岁男性，临床表现为全身浮肿、全心扩大、室间隔及室壁运动普遍性减弱、左心室舒张及收缩功能减低、右心室收缩功能减低。WES检测结果提示患儿携带PKP2基因c.119_122del(p.Leu40Argfs Ter 71)杂合移码变异与c.1978G>A(p.Gly660Arg)杂合错义变异。经Sanger测序验证，上述变异分别遗传自患儿父亲与母亲。PKP2基因c.119_122del变异在1000 Genomes、gnomAD及ExAC等数据库中未见收录；经SWISS-MODEL与PyMOL在线软件分析可能导致PKP2蛋白截短；根据美国医学遗传学与基因组学学会(ACMG)与ClinGen联合制订的相关指南，该变异被判定为可能致病性变异。PKP2基因c.1978G>A变异在1000 Genomes、gnomAD及ExAC等数据库中未见收录；应用REVEL、SIFT、CADD、MutationTaster及PolyPhen-2等在线软件预测为有害变异；经T-coffee与ESPriptv3.0在线服务器分析，该变异位点编码氨基酸在不同物种中高度保守；经SWISS-MODEL与PyMOL在线服务器分析，该变异可能影响蛋白功能；根据ACMG与ClinGen联合制订的相关指南，该变异被判定为可能致病性变异。 结论 PKP2基因c.119_122del(p.Leu40Argfs Ter 71)杂合移码变异与c.1978G>A(p.Gly660Arg)杂合错义变异可能是本研究ARVC患儿的遗传学病因。上述发现拓宽了PKP2基因的变异谱，为ARVC患者的诊断提供了依据。 Objective To explore the clinical and genetic characteristics of a child with Arrhythmogenic right ventricular cardiomyopathy (ARVC). Methods A 6-year-old boy with ARVC who had visited Fujian Provincial Children′s Hospital on August 23, 2022 was selected as the study subject. Relevant clinical data were collected, and peripheral venous blood samples were collected from the child and his parents for genetic testing through whole exome sequencing (WES). Sanger sequencing was carried out for family verification, and pathogenicity analysis was conducted for the candidate variants. Results The child had exhibited clinical symptoms including systemic edema, generalized heart enlargement, universal reduction of interventricular septum and ventricular wall movement, reduced left ventricular diastolic and systolic function, and reduced right ventricular systolic function. WES revealed that the child has harbored compound heterozygous variants of the PKP2 gene, namely c. 119_122del (p.Leu40ArgfsTer71) and c. 1978G>A (p.Gly660Arg), which were verified by Sanger sequencing to be respectively inherited from his father and mother. The c. 119_122del variant has not been recorded in the 1000 Genomes, gnomAD and ExAC databases, and was predicted to lead to truncation of the PKP2 protein by SWISS-MODEL and PyMOL online software and classified as likely pathogenic based on the guidelines jointly developed by the American College of Medical Genetics and Genomics (ACMG) and ClinGen. The c. 1978G>A variant has also not been recorded in the 1000 Genomes, gnomAD and ExAC databases, and was predicted to be deleterious by online software including REVEL, SIFT, CADD, Mutation Taster, and PolyPhen-2. The amino acid encoded by the variant site was highly conserved among various species by analysis using T-coffee and ESPriptv3.0 online servers. The variant may affect the protein function by SWISS-MODEL and PyMOL online server analysis, and was classified as likely pathogenic based on the guidelines jointly developed by the ACMG and ClinGen. Conclusion The compound heterozygous variants of c. 119_122del (p.Leu40ArgfsTer71) and c. 1978G>A (p.Gly660Arg) of thePKP2 gene probably underlay the ARVC in this child. Above finding has broadened the spectrum of PKP2 gene variants and provided a reference for the diagnosis and genetic counseling.
Objective To explore the clinical and genetic characteristics of a child with Arrhythmogenic right ventricular cardiomyopathy (ARVC). Methods A 6-year-old boy with ARVC who had visited Fujian Provincial Children′s Hospital on August 23, 2022 was selected as the study subject. Relevant clinical data were collected, and peripheral venous blood samples were collected from the child and his parents for genetic testing through whole exome sequencing (WES). Sanger sequencing was carried out for family verification, and pathogenicity analysis was conducted for the candidate variants. Results The child had exhibited clinical symptoms including systemic edema, generalized heart enlargement, universal reduction of interventricular septum and ventricular wall movement, reduced left ventricular diastolic and systolic function, and reduced right ventricular systolic function. WES revealed that the child has harbored compound heterozygous variants of the PKP2 gene, namely c. 119_122del (p.Leu40ArgfsTer71) and c. 1978G>A (p.Gly660Arg), which were verified by Sanger sequencing to be respectively inherited from his father and mother. The c. 119_122del variant has not been recorded in the 1000 Genomes, gnomAD and ExAC databases, and was predicted to lead to truncation of the PKP2 protein by SWISS-MODEL and PyMOL online software and classified as likely pathogenic based on the guidelines jointly developed by the American College of Medical Genetics and Genomics (ACMG) and ClinGen. The c. 1978G>A variant has also not been recorded in the 1000 Genomes, gnomAD and ExAC databases, and was predicted to be deleterious by online software including REVEL, SIFT, CADD, Mutation Taster, and PolyPhen-2. The amino acid encoded by the variant site was highly conserved among various species by analysis using T-coffee and ESPriptv3.0 online servers. The variant may affect the protein function by SWISS-MODEL and PyMOL online server analysis, and was classified as likely pathogenic based on the guidelines jointly developed by the ACMG and ClinGen. Conclusion The compound heterozygous variants of c. 119_122del (p.Leu40ArgfsTer71) and c. 1978G>A (p.Gly660Arg) of thePKP2 gene probably underlay the ARVC in this child. Above finding has broadened the spectrum of PKP2 gene variants and provided a reference for the diagnosis and genetic counseling.
Arrhythmogenic right ventricular cardiomyopathyPKP2 geneGenetic variations
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