HER2 deficiency causes a developmental disorder with growth retardation and craniofacial malformations.

Summary

Through multi-species functional validation, rare germline HER2 loss-of-function variants were shown to cause a human developmental syndrome (GRACE) with growth retardation and craniofacial malformations. Maternal exposure to a HER2 inhibitor reproduced similar defects in mice, highlighting a teratogenic risk of HER2-targeted therapy during pregnancy.

Key Findings

• Five rare germline HER2 variants were identified in unrelated families with growth and craniofacial anomalies from a 720-family cleft cohort.
• Variants impaired HER2 stability/localization/phosphorylation and reduced ERK signaling in cells; Xenopus assays failed to rescue development.
• Knock-in mice harboring a patient variant and mice with maternal tucatinib exposure recapitulated growth retardation and craniofacial defects.
• Defines GRACE syndrome and implicates HER2 as essential for human growth and craniofacial morphogenesis; warns of pregnancy risk with anti-HER2 drugs.

Clinical Implications

Genetic testing for HER2 variants should be considered in patients presenting with syndromic orofacial clefts and growth retardation; HER2-targeted therapies should be avoided during pregnancy due to potential teratogenicity.

Limitations

• Number of affected families with HER2 variants was small (n=5)
• Human pregnancy risk inference is based on mouse exposure models and requires clinical corroboration

Future Directions

Establish registries for pregnancy outcomes with HER2-targeted therapies; delineate genotype–phenotype correlations and variant penetrance; explore safe therapeutic alternatives during pregnancy.