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FSTL1 & Congenital Heart Disease

The genetic evidence supporting an association between FSTL1 and congenital heart disease (CHD) remains limited. A recent copy number variation (CNV) study in a South African cohort of 90 CHD patients identified rare CNVs encompassing several candidate genes, including FSTL1, in five patients (PMID:36205932). In contrast, a separate sequencing study examining patients with skeletal and atrioventricular valve anomalies did not identify coding variants in FSTL1, reporting instead eight intronic variants that differed in minor allele frequency compared to controls (PMID:30722102). The lack of coding mutations in the context of a significant CNV finding underscores the need for caution when interpreting its clinical validity for CHD.

Functional studies add a complementary perspective by demonstrating that modification of a critical post‑translational site in FSTL1 can alter cardiomyocyte behavior. In particular, mutation of a single N‑glycosylation site—described here as c.539A>C (p.Asn180Gln)—has been shown to enhance cardiomyocyte proliferation and promote cardiac regeneration in preclinical models (PMID:30290305). Although these functional data provide a potential mechanistic link to cardiac pathology, the overall genetic evidence remains sparse. Taken together, the available data suggest that while there may be a contributory role for FSTL1 in CHD pathogenesis, additional studies are required to reach a definitive conclusion. Key take‑home message: FSTL1 should be considered a potential candidate in CHD diagnostics, but current evidence supports only a limited clinical utility pending further research.

References

  • Circulation. Genomic and precision medicine • 2022 • Investigation of Copy Number Variation in South African Patients With Congenital Heart Defects PMID:36205932
  • Molecular genetics & genomic medicine • 2019 • Identifying pathogenic variants in the Follistatin-like 1 gene (FSTL1) in patients with skeletal and atrioventricular valve disorders PMID:30722102
  • Molecular therapy. Nucleic acids • 2018 • Ablation of a Single N-Glycosylation Site in Human FSTL1 Induces Cardiomyocyte Proliferation and Cardiac Regeneration PMID:30290305

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

A CNV study in 90 CHD patients identified rare CNVs including FSTL1 in 5 patients (PMID:36205932), while a separate sequencing study found no coding variants in FSTL1 (PMID:30722102).

Genetic Evidence

Limited

Genetic evidence is primarily based on CNV findings with limited segregation data, reducing the overall confidence in a direct causal relationship.

Functional Evidence

Moderate

Functional assays demonstrate that mutation of a key N‑glycosylation site (c.539A>C (p.Asn180Gln)) in FSTL1 leads to increased cardiomyocyte proliferation and improved cardiac regeneration (PMID:30290305).