Identification of a Novel FLNC Truncating Variant in Fetal Tetralogy of Fallot: A Case Report and Review of the Literature

<b>Background and Clinical Significance</b>: <i>FLNC</i> encodes filamin C, a muscle-scaffolding protein crucial for cardiac integrity. Pathogenic <i>FLNC</i> variants cause diverse cardiomyopathies (hypertrophic, dilated, restrictive, and arrhythmogenic) and myofibrillar myopathies, but their role in congenital cardiac malformations is unclear. Notably, <i>FLNC</i> has not been implicated in structural defects such as Tetralogy of Fallot (TOF) to date. <b>Case Presentation</b>: Two fetuses from the same family were prenatally diagnosed with TOF via ultrasound. The trio whole-exome sequencing of the second fetus and her parents identified a novel heterozygous truncating <i>FLNC</i> variant (NM_001458.5:c.1453C>T, p.Q485*). Sanger sequencing confirmed the same variant in the earlier TOF fetus. The mother carried the variant but was asymptomatic. <i>In vitro</i> mutagenesis in rat cardiomyocytes showed that the mutant <i>FLNC</i> construct produced markedly reduced FLNC proteins compared to the wild type and did not form abnormal cytoplasmic aggregates. <b>Conclusions</b>: We report on a novel <i>FLNC</i> truncating variant associated with fetal TOF, extending the spectrum of <i>FLNC</i>-related cardiac anomalies. The variable outcomes among variant carriers-from fetal TOF to adult cardiomyopathy or no clinical manifestations-underscore the complex genotype-phenotype correlations of filaminopathy. This case highlights the importance of comprehensive genetic evaluation in families with diverse cardiac phenotypes and suggests that additional genetic factors likely influence phenotypic expression.