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Case Reports
. 2024 Jun;12(6):e2486.
doi: 10.1002/mgg3.2486.

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

Lilia Kraoua  1 , Assaad Louati  2   3 , Sarra Ben Ahmed  4 , Nesrine Abida  1 , Monia Khemiri  4 , Khaled Menif  2   3 , Ridha Mrad  1 , Stéphane Zaffran  5 , Hager Jaouadi  5
Affiliations
Case Reports

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

Lilia Kraoua et al. Mol Genet Genomic Med. 2024 Jun.

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: Pathogenic TNNI3 variant; exome sequencing; lethal neonatal DCM.

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Conflict of interest statement

The authors declare no competing interests.

Figures

FIGURE 1
FIGURE 1
Family pedigree and Sanger sequencing results showing the homozygous deletionTNNI3 (NM_000363.5) : c.204delG; p.(Arg69AlafsTer8) in patients IV‐5 and IV‐6 and her heterozygous parents (III‐1 and III‐2).
FIGURE 2
FIGURE 2
Electrocardiogram of patient IV‐5 showing normal tracing at admission to the intensive unit care.
See this image and copyright information in PMC

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