NTRK3 – Congenital Heart Disease

Neurotrophic tyrosine kinase receptor C (NTRK3) encodes TrkC, a receptor essential for normal cardiogenesis in animal models. A high-resolution microarray study of 58 patients with congenital heart disease and additional anomalies identified potentially pathogenic copy-number variants in 12 individuals, including one CNV encompassing NTRK3 (PMID:22010865).

In a targeted sequencing analysis of 467 CHD patients, four rare heterozygous missense mutations in NTRK3 were found in four unrelated individuals with ventricular septal defects and were absent in ethnically matched controls (PMID:25196463). No familial segregation data were reported.

Functional assays in neuroblastoma cell lines expressing the TrkC p.Thr93Met variant (c.278C>T (p.Thr93Met)) demonstrated significantly reduced autophosphorylation in response to neurotrophin-3 and decreased downstream signaling, alongside altered cell growth under low-serum conditions (PMID:25196463).

These data support a loss-of-function mechanism for pathogenic NTRK3 alleles in CHD. Although no cardiac‐specific animal model data have been published, TrkC deficiency disrupts embryonic development broadly.

On balance, moderate genetic evidence (five probands: four missense and one CNV) combined with in vitro functional concordance justifies a Moderate clinical validity classification for NTRK3 in congenital heart disease.

Key Take-home: Rare NTRK3 variants impair TrkC activation and contribute to ventricular septal defects, informing diagnostic sequencing panels and functional follow‐up studies.

References

• Human mutation • 2014 • Mutations in NTRK3 suggest a novel signaling pathway in human congenital heart disease. PMID:25196463
• Congenital heart disease • 2011 • Microdeletions and microduplications in patients with congenital heart disease and multiple congenital anomalies. PMID:22010865

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