{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:15:11Z","timestamp":1790792111678,"version":"4.1.0"},"reference-count":37,"publisher":"American Society for Clinical Investigation","issue":"12","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":46,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Beijing Natural Science Foundation","award":["Z240020"],"award-info":[{"award-number":["Z240020"]}]},{"name":"Key Research and Development Project of the Shaanxi Province Health Scientific Research and Innovation Capacity Enhancement Program","award":["2025YF-05"],"award-info":[{"award-number":["2025YF-05"]}]},{"name":"Shaanxi Provincial Youth Science and Technology Star Program","award":["2025ZC-KJXX-140"],"award-info":[{"award-number":["2025ZC-KJXX-140"]}]},{"name":"the IIT Clinical Research Fund of The Second Affiliated Hospital of Xi\u2019an Jiaotong University","award":["T-007"],"award-info":[{"award-number":["T-007"]}]},{"name":"Fundamental Research Funds for the Peking University","award":["PKU2022XGK001"],"award-info":[{"award-number":["PKU2022XGK001"]}]},{"name":"National Key Research and Development Program of China","award":["2022YFA1206103"],"award-info":[{"award-number":["2022YFA1206103"]}]},{"name":"Peking University Medicine plus X Pilot Program-Platform Construction Project","award":["2024YXXLHPT012"],"award-info":[{"award-number":["2024YXXLHPT012"]}]},{"name":"Clinical Medicine Plus X - Young Scholars Project of Peking University, and the Fundamental Research Funds for the Central Universities","award":["PKU2024LCXQ005"],"award-info":[{"award-number":["PKU2024LCXQ005"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82572120"],"award-info":[{"award-number":["82572120"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82572120,32070803,82170916,32370859,82373594,82370909,82001030"],"award-info":[{"award-number":["82572120,32070803,82170916,32370859,82373594,82370909,82001030"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,15]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>HER2<\/jats:italic>\n                    variants in 5 unrelated families with growth deficits, orofacial clefts, and other craniofacial, skeletal, and auditory anomalies. In\n                    <jats:italic>Xenopus<\/jats:italic>\n                    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\n                    <jats:italic>HER2<\/jats:italic>\n                    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\u2019s 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.\n                  <\/jats:p>","DOI":"10.1172\/jci199043","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T16:00:15Z","timestamp":1777564815000},"source":"Crossref","is-referenced-by-count":2,"title":["HER2 deficiency causes a developmental disorder with growth retardation and craniofacial malformations"],"prefix":"10.1172","volume":"136","author":[{"given":"Huaxiang","family":"Zhao","sequence":"first","affiliation":[{"name":"Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."},{"name":"Department of Transfusion Medicine, The Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."},{"name":"Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China."},{"name":"Department of Orthodontics, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Wang","sequence":"additional","affiliation":[{"name":"Research Center for Industries of the Future, Westlake University, Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China."},{"name":"Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhua","family":"Jiao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."},{"name":"Department of Orthodontics, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Xi\u2019an Children\u2019s Hospital, The Affiliated Children\u2019s Hospital, Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, China."},{"name":"National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory for Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, NMPA Key Laboratory for Dental Materials, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"He","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Health Science Center, Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengkai","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Health Science Center, Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbin","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, Stomatological Center, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfei","family":"Jia","sequence":"additional","affiliation":[{"name":"Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."},{"name":"Department of Orthodontics, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianying","family":"Kong","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and 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