{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T06:58:29Z","timestamp":1767941909532,"version":"3.49.0"},"reference-count":20,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"\n Background<\/jats:title>\n Bainbridge\u2013Ropers syndrome (BRPS, OMIM #615485) and the 15q11.2 BP1-BP2 microdeletion syndrome (OMIM #615656) are distinct genetic aetiologies of neurodevelopmental disorder Dual diagnosis of both entities in a single patient is extremely rare, and the underlying synergistic pathogenesis remains poorly understood.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We report a 7-month-old boy presenting with severe global developmental delay, hypotonia, feeding difficulties, microcephaly and recurrent respiratory infections. Whole-exome sequencing (WES) was performed and a protein\u2013protein-interaction (PPI) network was constructed using the STRING database to aid molecular diagnosis. Clinical management and 7-month outcome are described.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n WES identified a\n de novo<\/jats:italic>\n nonsense mutation in\n ASXL3<\/jats:italic>\n (c.1094C&gt;G, p. Ser365*) and a 1.22-Mb 15q11.2 microdeletion (BP1-BP2) inherited from the asymptomatic father, establishing a dual diagnosis. The PPI network revealed no direct or high-confidence (&gt;0.4) interactions between\n ASXL3<\/jats:italic>\n and the 15q11.2 BP1-BP2 microdeletion-encoded proteins\n CYFIP1<\/jats:italic>\n ,\n NIPA1<\/jats:italic>\n ,\n NIPA2<\/jats:italic>\n or\n TUBGCP5<\/jats:italic>\n , indicating convergence at the pathway rather than the complex level.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n The 15q11.2 BP1-BP2 microdeletion acts as a genetic modifier that may amplify the phenotypic expression caused by the core mutation in the ASXL3 gene. Haploinsufficiency of\n CYFIP1<\/jats:italic>\n ,\n NIPA1<\/jats:italic>\n ,\n NIPA2<\/jats:italic>\n , and\n TUBGCP5<\/jats:italic>\n increases neurodevelopmental susceptibility, while the\n de novo<\/jats:italic>\n truncating mutation in\n ASXL3<\/jats:italic>\n drives severe epigenetic dysregulation. Together, they precipitate the profound phenotype observed here. This case suggests that multilocus pathogenic variation can generate a blended, severe phenotype and underscores the need to consider polygenic burden plus gene\u2013environment interactions in complex NDD. We proposed a \u201ccore mutation - gene regulator - environment\u201d synergy hypothesis model, which is of significant guidance value for genetic counseling and personalized clinical management.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fgene.2025.1674158","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T12:24:48Z","timestamp":1765455888000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Synergistic effects of an ASXL3 mutation and a 15q11.2 BP1-BP2 microdeletion in a severe neurodevelopmental phenotype"],"prefix":"10.3389","volume":"16","author":[{"given":"Mingkai","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanfang","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chanjuan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhou","family":"Chu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guohong","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1136\/jmedgenet-2016-104360","article-title":"Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature","volume":"54","author":"Balasubramanian","year":"2017","journal-title":"J. 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