Abstract
The human epidermal growth factor receptor 2 (HER2) is a major therapeutic target in cancer. While the oncogenic effects of HER2 hyperactivation are well characterized, the biological consequences of its deficiency remain poorly defined. Here, through exome sequencing analyses of a cohort of 720 families affected by isolated or syndromic orofacial clefts, we unexpectedly identified 5 distinct rare germline HER2 variants in 5 unrelated families with growth deficits, orofacial clefts, and other craniofacial, skeletal, and auditory anomalies. In Xenopus embryos, these variants failed to recapitulate the developmental effects of WT HER2. In cultured cells, they disrupted HER2 protein stability, membrane localization, or site-specific phosphorylation, resulting in diminished ERK signaling. Strikingly, knock-in mice expressing a patient-derived HER2 variant and mice maternally exposed to Tucatinib, a recently approved anti-HER2 drug, both replicated patient phenotypes: delayed growth and diverse craniofacial abnormalities, including ocular dysgenesis, short jaws, and cleft palate. Collectively, our findings define a developmental disorder that we designate GRACE syndrome (Growth Retardation and Craniofacial Malformations Caused by HER2 Deficiency), establish HER2’s essential role in human growth and craniofacial morphogenesis, and reveal that HER2-targeted therapies during pregnancy can induce craniofacial defects and lifelong growth impairment in fetuses.
Authors
Huaxiang Zhao, Pan Wang, Yuhua Jiao, Huimei Huang, Min Yu, Qing He, Chengkai Pan, Shuang Guo, Wenbin Huang, Yunfei Jia, Qianying Kong, Huifang Peng, Yandong Han, Yuxia Hou, Zhanping Ren, Yongwei Tao, Fei Huang, Hongwei Jiang, Shan Sun, Yanying Dong, Jiuxiang Lin, Chunyan Yin, Xuechen Zhu, Feng Chen, Yi Ding
Figure 2
Patient variants impair HER2/ERK signaling.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)