ADAM17 – Congenital Heart Disease

ADAM17 encodes a transmembrane metalloprotease (TACE) responsible for ectodomain shedding of multiple substrates, including growth factors critical for cardiac development. Its role in ErbB signaling and ventricular structure has been established in animal models but human genetic evidence linking ADAM17 to congenital heart disease (CHD) has been limited. Recent sequencing studies in CHD cohorts have begun to implicate ADAM17 variants in disease etiology, with functional validation suggesting a direct pathogenic mechanism.

In a targeted sequencing screen of 80 tetralogy of Fallot (TOF) patients, three heterozygous missense variants in ADAM17 were identified exclusively in unrelated TOF probands and absent from 480 ethnically matched controls and public databases (3 probands) (PMID:30610007). No familial segregation data were reported, consistent with a de novo or oligogenic model of inheritance. These findings represent the first report of ADAM17 variants in human TOF, the most common cyanotic CHD subtype.

Among the identified variants, c.124T>G (p.Tyr42Asp) was shown to impair heparin-binding EGF-like growth factor (HB-EGF) shedding without affecting Notch signaling (PMID:30610007). This variant lies in the prodomain region of ADAM17, a domain crucial for proper folding and substrate access. In silico predictions and absence from ExAC support its pathogenicity.

Inheritance is consistent with an autosomal dominant, oligogenic contribution to CHD risk, as probands carried heterozygous ADAM17 variants without reported biallelic hits. No additional affected relatives were described, and segregation analysis remains to be performed. The low number of probands and lack of familial data currently preclude a definitive genetic classification.

Functional validation using CRISPR/Cas9-engineered human embryonic stem cells differentiated to cardiomyocytes demonstrated that KI of Y42D or L659P variants, as well as complete ADAM17 knockout, induces cardiomyocyte hypertrophy with disorganized sarcomeres. RNA-seq and shedding assays confirmed loss-of-function in HB-EGF/ErbB signaling, recapitulating the right ventricular hypertrophy seen in TOF patients (PMID:30610007). These data provide moderate experimental support for a pathogenic mechanism through impaired growth factor release.

In summary, heterozygous ADAM17 missense variants are observed in a small number of unrelated TOF probands and functionally validated to disrupt HB-EGF shedding and drive cardiomyocyte hypertrophy. While genetic segregation remains untested, concordant in vitro modeling supports a causal role in CHD. Further familial studies and independent replication are needed to reach a definitive classification. Key Take-home: ADAM17 loss-of-function variants represent a potential molecular cause of CHD via impaired HB-EGF/ErbB signaling, offering a target for future diagnostic and therapeutic strategies.

References

• Clinical science (London, England : 1979) • 2019 • Rare mutations of ADAM17 from TOFs induce hypertrophy in human embryonic stem cell-derived cardiomyocytes via HB-EGF signaling. PMID:30610007

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