{Reference Type}: Journal Article
{Title}: Homozygous TNNI3 frameshift variant in a consanguineous family with lethal infantile dilated cardiomyopathy.
{Author}: Kraoua L;Louati A;Ahmed SB;Abida N;Khemiri M;Menif K;Mrad R;Zaffran S;Jaouadi H;
{Journal}: Mol Genet Genomic Med
{Volume}: 12
{Issue}: 6
{Year}: 2024 Jun
{Factor}: 2.473
{DOI}: 10.1002/mgg3.2486
{Abstract}: <B>BACKGROUND: </B>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.<BR><B>UNASSIGNED: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.