{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:44:55Z","timestamp":1792111495081,"version":"4.4.0"},"reference-count":40,"publisher":"The Endocrine Society","issue":"11","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"publisher","award":["2024YFA1802701"],"award-info":[{"award-number":["2024YFA1802701"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82301943"],"award-info":[{"award-number":["82301943"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82270826"],"award-info":[{"award-number":["82270826"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82200874"],"award-info":[{"award-number":["82200874"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170802"],"award-info":[{"award-number":["82170802"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070816"],"award-info":[{"award-number":["82070816"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2022J01438"],"award-info":[{"award-number":["2022J01438"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003395","name":"Shanghai Municipal Education Commission","doi-asserted-by":"publisher","award":["ZDCX20210901"],"award-info":[{"award-number":["ZDCX20210901"]}],"id":[{"id":"10.13039\/501100003395","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003395","name":"Shanghai Municipal Education Commission","doi-asserted-by":"publisher","award":["ZDCX20212501"],"award-info":[{"award-number":["ZDCX20212501"]}],"id":[{"id":"10.13039\/501100003395","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>Congenital hypothyroidism (CH) is a major preventable cause of developmental and cognitive impairment. Current genetic testing identifies causative variants for only half of cases, leaving the majority without a molecular diagnosis. Although animal studies implicate Notch signaling in thyroid development, its role in human CH remains unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate whether Notch pathway variants contribute to genetically unexplained CH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Genetic screening using whole-exome sequencing with zebrafish functional validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Setting<\/jats:title>\n                    <jats:p>Endocrinology outpatient clinic at Shanghai Ninth People's Hospital.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Patients or Other Participants<\/jats:title>\n                    <jats:p>A total of 781 unrelated Chinese patients with CH. After identifying variants in 21 known causative genes in 364 patients, the remaining 417 unsolved cases were screened for variants in 77 Notch signaling pathway genes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main Outcome Measure(s)<\/jats:title>\n                    <jats:p>Identification of biallelic Notch pathway variants; functional validation through zebrafish morpholino knockdown experiments assessing thyroid morphology and hormone production; clinical phenotype including thyroid function parameters, thyroid morphology, and levothyroxine dosage requirements; comparison with 267 DUOX2 patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified biallelic variants in 11 Notch pathway genes (NEURL1, CNTN6, NOTCH3, DTX1, DVL1, DTX2, ATXN1, SPEN, CTBP2, NCOR2, MAMLD1) in 21 patients. Zebrafish knockdown provided functional support for the potential pathogenic role of these genes, showing reduced thyroglobulin expression, abnormal morphology, elevated tsh levels, and decreased T4. Notch-variant patients showed higher initial FT4 but required significantly higher levothyroxine doses than DUOX2 patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Notch pathway variants may contribute to approximately 5% of genetically unexplained CH. Variants across multiple pathway components collectively impair thyroid function. These findings suggest a potential expansion of CH genetic architecture and suggest that Notch-variant patients may require enhanced hormone replacement despite milder initial presentation, warranting pathway-specific screening.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgag208","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T11:19:04Z","timestamp":1779794344000},"page":"3111-3127","source":"Crossref","is-referenced-by-count":2,"title":["First large-scale screening of Notch biallelic variants implicates novel candidate genes in congenital hypothyroidism"],"prefix":"10.1210","volume":"111","author":[{"given":"Feng-Yao","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine , Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Yang","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University , Shanghai 200032 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine , Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Gang","family":"Tian","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine, Bengbu Medical University , Bengbu 233030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye-Ke","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 200080 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren-Jie","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine , Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui-Feng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Urology, Fudan University Shanghai Cancer Center , Shanghai 200032 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine , Shanghai 200011 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Yuan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine , Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Yu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical 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Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine , Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine , Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Yida","family":"Nulali","sequence":"additional","affiliation":[{"name":"Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine , Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng-Xue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine , Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine , Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Yang","family":"Song","sequence":"additional","affiliation":[{"name":"Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine and Department of Thoracic Surgery of Ruijin Hospital, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Han","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 200011 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine , Shanghai 200011, 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