PDF(Pubmed)
Abstract：
BACKGROUND: Dilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle, systolic dysfunction, and normal or reduced thickness of the left ventricular wall. It is a leading cause of heart failure and cardiac death at a young age. Cases with neonatal onset DCM were correlated with severe clinical presentation and poor prognosis. A monogenic molecular etiology accounts for nearly half of cases.
UNASSIGNED: Here, we report a family with three deceased offspring at the age of 1 year old. The autopsy of the first deceased infant revealed a DCM. The second infant presented a DCM phenotype with a severely reduced Left Ventricular Ejection Fraction (LVEF) of 10%. Similarly, the third infant showed a severe DCM phenotype with LVEF of 30% as well, in addition to eccentric mitral insufficiency.
RESULTS: Exome sequencing was performed for the trio (the second deceased infant and her parents). Data analysis following the autosomal dominant and recessive patterns of inheritance was carried out along with a mitochondrial pathways-based analysis. We identified a homozygous frameshift variant in the TNNI3 gene (c.204delG; p.(Arg69AlafsTer8)). This variant has been recently reported in the ClinVar database in association with cardiac phenotypes as pathogenic or likely pathogenic and classified as pathogenic according to ACMG.
CONCLUSIONS: Genetic counseling was provided for the family and a prenatal diagnosis of choronic villus was proposed in the absence of pre-implantation genetic diagnosis possibilities. Our study expands the case series of early-onset DCM patients with a protein-truncating variant in the TNNI3 gene by reporting three affected infant siblings.
UNASSIGNED: Here, we report a family with three deceased offspring at the age of 1 year old. The autopsy of the first deceased infant revealed a DCM. The second infant presented a DCM phenotype with a severely reduced Left Ventricular Ejection Fraction (LVEF) of 10%. Similarly, the third infant showed a severe DCM phenotype with LVEF of 30% as well, in addition to eccentric mitral insufficiency.
RESULTS: Exome sequencing was performed for the trio (the second deceased infant and her parents). Data analysis following the autosomal dominant and recessive patterns of inheritance was carried out along with a mitochondrial pathways-based analysis. We identified a homozygous frameshift variant in the TNNI3 gene (c.204delG; p.(Arg69AlafsTer8)). This variant has been recently reported in the ClinVar database in association with cardiac phenotypes as pathogenic or likely pathogenic and classified as pathogenic according to ACMG.
CONCLUSIONS: Genetic counseling was provided for the family and a prenatal diagnosis of choronic villus was proposed in the absence of pre-implantation genetic diagnosis possibilities. Our study expands the case series of early-onset DCM patients with a protein-truncating variant in the TNNI3 gene by reporting three affected infant siblings.
摘要：
背景：扩张型心肌病（DCM）的特征是左心室扩张，收缩功能障碍,左心室壁厚度正常或减小。它是年轻时心力衰竭和心脏死亡的主要原因。新生儿发病的DCM病例与严重的临床表现和不良预后有关。单基因分子病因占病例的近一半。
■这里，我们报告了一个有三个死亡后代的家庭，年龄为1岁。第一个死亡婴儿的尸检显示DCM。第二个婴儿表现为DCM表型，左心室射血分数（LVEF）严重降低10％。同样，第三个婴儿表现出严重的DCM表型，LVEF也为30％，除了偏心二尖瓣关闭不全。
结果：对三人组（第二个死亡婴儿及其父母）进行了外显子组测序。在遗传的常染色体显性和隐性模式之后进行数据分析以及基于线粒体途径的分析。我们在TNNI3基因中鉴定了纯合移码变体(c.204delG;p.(Arg69AlafsTer8))。最近在ClinVar数据库中报道了这种变异与心脏表型相关，为致病性或可能致病性，并根据ACMG分类为致病性。
结论：为家庭提供了遗传咨询，并且在没有植入前遗传诊断可能性的情况下，提出了对绒毛绒毛的产前诊断。我们的研究通过报告三个受影响的婴儿兄弟姐妹，扩展了在TNNI3基因中具有蛋白质截断变体的早发性DCM患者的病例系列。
■这里，我们报告了一个有三个死亡后代的家庭，年龄为1岁。第一个死亡婴儿的尸检显示DCM。第二个婴儿表现为DCM表型，左心室射血分数（LVEF）严重降低10％。同样，第三个婴儿表现出严重的DCM表型，LVEF也为30％，除了偏心二尖瓣关闭不全。
结果：对三人组（第二个死亡婴儿及其父母）进行了外显子组测序。在遗传的常染色体显性和隐性模式之后进行数据分析以及基于线粒体途径的分析。我们在TNNI3基因中鉴定了纯合移码变体(c.204delG;p.(Arg69AlafsTer8))。最近在ClinVar数据库中报道了这种变异与心脏表型相关，为致病性或可能致病性，并根据ACMG分类为致病性。
结论：为家庭提供了遗传咨询，并且在没有植入前遗传诊断可能性的情况下，提出了对绒毛绒毛的产前诊断。我们的研究通过报告三个受影响的婴儿兄弟姐妹，扩展了在TNNI3基因中具有蛋白质截断变体的早发性DCM患者的病例系列。
