{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:33:30Z","timestamp":1792172010691,"version":"4.4.0"},"reference-count":44,"publisher":"American Society for Clinical Investigation","issue":"4","license":[{"start":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T00:00:00Z","timestamp":1740355200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation (NRF) of Korea","doi-asserted-by":"crossref","award":["2022R1A2C3002917"],"award-info":[{"award-number":["2022R1A2C3002917"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation (NRF) of Korea","doi-asserted-by":"crossref","award":["2022R1A4A1031336"],"award-info":[{"award-number":["2022R1A4A1031336"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"crossref","award":["RS-2024-00404555"],"award-info":[{"award-number":["RS-2024-00404555"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"crossref","award":["MD-PhD\/Medical Scientist Training Program"],"award-info":[{"award-number":["MD-PhD\/Medical Scientist Training Program"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,24]]},"abstract":"<jats:p>\n                    Craniosynostosis (CRS) is characterized by the development of abnormal cranial suture ossification and premature fusion. Despite the identification of several associated genetic disorders, the genetic determinants of CRS remain poorly understood. In this study, we conducted integrative analyses on 225 exomes, comprising 121 CRS probands and 104 parental exomes (52 trios). These analyses encompassed de novo and pathogenic variants, and digenic combinations within haploinsufficient genes harboring rare variants. Our analysis unveils a shared molecular network between genes associated with CRS and those linked to skeletal and neurodevelopmental disorders, with a notable enrichment of deleterious variants within haploinsufficient genes. Additionally, we identified a unique digenic pair (\n                    <jats:italic>IL6ST<\/jats:italic>\n                    and\n                    <jats:italic>TRPS1<\/jats:italic>\n                    ) within haploinsufficient genes that was present in 2 patients with nonsyndromic CRS but absent in parents or 1,048 population controls. In vitro experiments provided evidence that the identified missense variants were hypomorphs, and accelerated bone mineralization could result from the additive effects of diminished\n                    <jats:italic>IL6ST<\/jats:italic>\n                    and\n                    <jats:italic>TRPS1<\/jats:italic>\n                    activities in osteoblasts. Overall, our study underscores the important role of rare variations in haploinsufficient genes and suggests that in a subset of undiagnosed patients, the CRS phenotype may arise from multiple genetic variations.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.176985","type":"journal-article","created":{"date-parts":[[2025,2,23]],"date-time":"2025-02-23T14:00:45Z","timestamp":1740319245000},"source":"Crossref","is-referenced-by-count":3,"title":["Digenic impairments of haploinsufficient genes in patients with craniosynostosis"],"prefix":"10.1172","volume":"10","author":[{"given":"Jung Woo","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Graduate School of Medical Science Brain Korea 21 Project,"},{"name":"Department of Pediatric Neurosurgery, Craniofacial Reforming and Reconstruction Clinic,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihoon 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