NOTCH1 – Familial Bicuspid Aortic Valve

In a study of 11 Italian index patients with familial bicuspid aortic valve, two novel NOTCH1 variants were identified: c.851C>T (p.Pro284Leu) and p.Tyr1619Ter, each in unrelated families, segregating with disease and absent in 200 ethnically matched controls (PMID:23578328). No pathogenic variants were detected in GATA5, TGFBR1, or TGFBR2. These findings support an autosomal dominant inheritance with haploinsufficiency of NOTCH1 as the likely mechanism. NOTCH1 encodes a single-pass transmembrane receptor requiring sequential proteolytic S2/S3 cleavages for release of the intracellular domain and transcriptional activation; disruption of this processing inhibits NICD nuclear translocation and downstream signaling (PMID:8643690). Although general Notch1 function is well characterized, no BAV‐specific functional or animal models have been reported. Overall, the current evidence yields a Limited clinical validity classification for NOTCH1 in familial bicuspid aortic valve. Key take-home: NOTCH1 sequencing should be incorporated into genetic testing and counseling for families with bicuspid aortic valve.

References

• BMC medical genetics | 2013 | Sequencing of NOTCH1, GATA5, TGFBR1 and TGFBR2 genes in familial cases of bicuspid aortic valve. PMID:23578328
• Proceedings of the National Academy of Sciences of the United States of America | 1996 | Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain. PMID:8643690

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