Homozygous TNNI3 frameshift variant in a consanguineous family with lethal infantile dilated cardiomyopathy

Abstract

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. Family description 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. Conclusion 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.

Keywords

• exome sequencing
• lethal neonatal DCM
• Pathogenic TNNI3 variant