Sarcomere gene variants did not improve cardiac function in pediatric patients with dilated cardiomyopathy from Japanese cohorts

Abstract

Background: Dilated cardiomyopathy (DCM) is a progressive myocardial disorder characterized by impaired cardiac contraction and ventricular dilation. Some patients with DCM could manifest improvement in these abnormalities called left ventricular reverse remodeling (LVRR). However, the detailed association between genotypes and clinical outcomes, including LVRR, particularly among pediatric patients, remains uncertain. Methods: We prospectively enrolled pediatric patients with DCM from Japanese multi-institutional centers between 2014 and 2023. We identified DCM-related genes and explored the association between gene variants and clinical outcomes, including LVRR, which was defined as any increase in left ventricular ejection fraction during the observation period. Results: A total of 123 pediatric patients (62 males; mean age of 8 months [range, 1?51 months]) were retrospectively enrolled. There were 50 pathogenic variants in 45 patients (35.0%). The most identified gene was MYH7 (14.0%), followed by RYR2 (12.0%), and TPM1 (8.0%). A novel variant in the CASZ1 gene (NM_001079843.2 c.3356G>A, p. Trp1119Ter) was identified. LVRR was achieved in 47.5% of patients. In patients with sarcomere gene variants, the left ventricular ejection fraction remained unchanged (31.4% to 39.8%, P = 0.1913), whereas it significantly increased in patients with non-sarcomere gene variants (33.4% to 47.8%, P = 0.0466) and in patients without gene variants (33.6% to 54.1%, P = 0.003). Conclusions: Pediatric patients with DCM exhibited a marked genetic heterogeneity with a different landscape from adults with DCM. LVRR was not uniform across functional gene groups, opening the door to tailor-made gene-guided prediction in pediatric patients with DCM.