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FOXP1 – Congenital Heart Disease

The transcription factor FOXP1 has been implicated in congenital heart disease through heterozygous loss-of-function alleles. In a cohort of 82 patients with atrioventricular septal defects or hypoplastic left heart syndrome, one patient harbored an ~0.3 Mb monoallelic deletion deleting exons 1–4 and two unrelated patients carried a heterozygous c.1702C>T (p.Pro568Ser) variant, absent in 287 controls but present at 0.2% in dbSNP (3 probands) (PMID:23766104). FOXP1 variants arose de novo or as rare alleles, with no familial segregation data.

Functional studies of the orthologous murine Foxp1 p.Pro596Ser protein revealed deficits in luciferase reporter repression and resulted in increased cardiomyoblast proliferation and elevated Nkx2.5 expression, concordant with a haploinsufficiency mechanism (PMID:23766104). Moreover, de novo damaging variants in FOXP1 were enriched among 3 684 CHD subjects compared to 1 789 controls, with FOXP1 ranking among the top 12 genes contributing to cardiac connectome disruption (PMID:32341405).

ClinGen classification of the FOXP1–congenital heart disease association is Limited, supported by three unrelated probands with heterozygous deletion or missense variants and no segregation data. Genetic evidence is Limited (three probands with FOXP1 variants in CHD; no familial segregation) and functional evidence is Moderate (reporter assays and proliferative phenotypes in cardiomyoblasts). Additional independent case series and segregation studies are needed to elevate clinical validity. Key take-home: FOXP1 haploinsufficiency is a candidate molecular cause of congenital heart disease warranting targeted sequencing in sporadic AVSD or hypoplastic left heart syndrome cases.

References

  • Human Mutation • 2013 • Genetic abnormalities in FOXP1 are associated with congenital heart defects. PMID:23766104
  • Scientific Reports • 2020 • De novo damaging variants associated with congenital heart diseases contribute to the connectome. PMID:32341405

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Heterozygous deletion and two missense variants in three unrelated CHD probands with no familial segregation ([PMID:23766104])

Genetic Evidence

Limited

Three probands with FOXP1 variants in CHD; no segregation data ([PMID:23766104])

Functional Evidence

Moderate

Luciferase reporter assays and cardiomyoblast studies demonstrate a haploinsufficiency mechanism ([PMID:23766104])