[A novel TPM1 variant causing Dilated cardiomyopathy in a child: A case report and literature review].

OBJECTIVE: To explore the clinical manifestations and characteristics of TPM1 gene variants causing Dilated cardiomyopathy (DCM) in children. METHODS: This study focused on a pediatric patient diagnosed with DCM associated with a TPM1 gene variant, who presented at the Pediatric Cardiology Department of Women and Children's Hospital of Ningbo University on October 1, 2024. A retrospective analysis of the clinical data was conducted. Peripheral blood samples were collected from the patient and both parents. Following extraction of genomic DNA, whole exome sequencing was carried out. Candidate variant was validated by Sanger sequencing in the family trio. Structural prediction and analysis of the mutant TPM1 protein were carried out using AlphaFold and PyMOL. In addition, a systematic literature review was conducted to summarize the clinical manifestations and genetic characteristics of DCM cases linked to TPM1 variants. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: EC2024-143). RESULTS: The patient, a 2-year-old girl, presented with delayed motor development. Colored Doppler ultrasound revealed left ventricular enlargement with slight endocardial thickening, mild-to-moderate mitral regurgitation, and reduced left ventricular systolic function. Whole exome sequencing revealed that she has harbored a heterozygous c.82_84del (p.Asp28del) variant of the TPM1 gene, which was detected in neither parent, suggesting a de novo origin or parental germline mosaicism. The three-dimensional structure of the TPM1 protein predicted by AlphaFold was analyzed in PyMOL, demonstrating that the variant may result in deletion of aspartic acid at position 28 (Asp28) and replacement with lysine (Lys28), forming new hydrogen bond interactions with residues Glu24, Ala31, and Glu32. A literature review has identified 10 English and 1 Chinese publication, collectively reporting 30 patients (including the present case) and 12 distinct TPM1 variants. Except for the deletion variant in this study, all others were missense variants, with the most common one being c.250G>A (p.Asp84Asn). Clinically, affected infants typically manifested as delayed motor/growth development, feeding difficulties, and dyspnea, while adult patients commonly presented with exertional dyspnea, palpitations, and dizziness as initial symptoms. CONCLUSION: This study has identified a de novo TPM1 variant c.82_84del (p.Asp28del) as a novel cause of pediatric DCM. Early genetic testing is crucial for the diagnosis, clinical management, and genetic counseling. Above finding has also enriched the mutational spectrum of TPM1-associated cardiomyopathy.