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Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect characterized by ventricular septal defect, pulmonary stenosis, overriding aorta, and right ventricular hypertrophy. Heterozygous variants in FLT4 (VEGFR3) have emerged as significant contributors to TOF susceptibility in multiple large‐scale sequencing studies. FLT4‐related TOF shows an autosomal dominant inheritance with incomplete penetrance, distinct from the dominant negative variants causing Milroy lymphedema.
In a cohort of 829 nonsyndromic TOF patients, FLT4 variants were found in 21 probands (2.4%) including loss‐of‐function and missense changes ([PMID:30582441]). A separate analysis of 175 adults with TOF from a single center identified nine probands (5.1%) harboring novel FLT4 loss‐of‐function or predicted damaging variants, and replication in ten families confirmed three independent FLT4 alleles ([PMID:30232381]). In an exome reanalysis of 811 TOF probands, likely pathogenic FLT4 variants were reported in 14 individuals (1.7%), reinforcing the gene’s role in TOF ([PMID:34328347]).
Segregation studies in two unrelated families demonstrated cosegregation of heterozygous FLT4 splice‐site variants with TOF phenotypes, confirming autosomal dominant transmission with variable expressivity ([PMID:39870876]). The spectrum of FLT4 variants includes canonical loss‐of‐function alleles (nonsense, frameshift, large deletions), splice‐site disruptions, and missense substitutions clustering in the tyrosine kinase domains. No founder alleles have been reported, and population frequencies are below disease thresholds in gnomAD.
Functional assessment in primary human endothelial cells and zebrafish models revealed that FLT4 TOF‐associated variants cause perinuclear receptor aggregation, activate proteostatic and metabolic stress pathways, and impair cardiac looping and heart size. These phenotypes were rescued by wild‐type FLT4 mRNA but not by TOF alleles, demonstrating a haploinsufficiency mechanism in cardiogenesis distinct from the dominant negative effect in Milroy disease ([PMID:38713105]).
To date, there are no conflicting reports disputing FLT4’s involvement in TOF, and variant‐specific cellular and animal models provide concordant evidence for a loss‐of‐function mechanism. While additional rare FLT4 alleles continue to be cataloged, current data meet the ClinGen criteria for a Strong gene–disease association based on multiple independent cohorts, diverse variant classes, segregation data, and robust functional concordance.
Key Take-home: FLT4 haploinsufficiency accounts for ~2–5% of nonsyndromic TOF cases, supporting inclusion of FLT4 in clinical genetic testing panels to inform diagnosis, family counseling, and potential mechanistic therapies.
Gene–Disease AssociationStrongIdentification of FLT4 variants in 21/829, 9/175, and 14/811 unrelated TOF probands ([PMID:30582441], [PMID:30232381], [PMID:34328347]); segregation in two families; concordant functional mechanism. Genetic EvidenceStrong44 unrelated TOF cases with diverse loss‐of‐function and missense FLT4 alleles across three cohorts; autosomal dominant inheritance with incomplete penetrance; reached ClinGen genetic cap. Functional EvidenceStrongCellular and zebrafish models demonstrate FLT4 TOF variants cause receptor aggregation and cardiac developmental defects rescued by wild-type mRNA, confirming haploinsufficiency ([PMID:38713105]). |