{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T06:57:20Z","timestamp":1767769040265,"version":"3.48.0"},"reference-count":12,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"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. Neurosci."],"abstract":"\n Introduction<\/jats:title>\n \n Buratti-Harel syndrome (BURHAS) is a rare autosomal dominant neurodevelopmental disorder caused by\n SIAH1<\/jats:italic>\n (Siah1 E3 ubiquitin ligase) variants, characterized by infantile hypotonia, global developmental delay, and variable multisystem involvement. To date, 13 pathogenic\n SIAH1<\/jats:italic>\n variants have been reported in 13 patients, but the functional and phenotypic implications of mutations in the\n SIAH1<\/jats:italic>\n zinc finger domain remain poorly characterized. This study included a Chinese pediatric patient with unexplained neurodevelopmental and multisystem abnormalities.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Trio whole-exome sequencing (WES) was performed to identify potential causative variants. Structural modeling was used to analyze the impact of the identified variant on\n SIAH1<\/jats:italic>\n protein structure. Additionally, a comparative genotype-phenotype analysis was conducted on 14 genetically confirmed BURHAS cases (including the present patient).\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A\n de novo<\/jats:italic>\n missense variant [c.288C &gt; G (p.Phe96Leu)] in the zinc finger domain of\n SIAH1<\/jats:italic>\n was identified in the patient. Structural modeling revealed that this variant destabilized the zinc finger domain (DDG = \u20132.09 kcal\/mol), which may disrupt the ZnF-1 domain function by impairing zinc ion-mediated structural stability. Comparative analysis of 14 genetically confirmed cases (including this study) demonstrated a genotype-phenotype correlation: zinc finger domain variants (\n n<\/jats:italic>\n = 4) exhibited broader phenotypic heterogeneity compared to RING domain variants (\n n<\/jats:italic>\n = 7), which were enriched for severe developmental delay and reproductive anomalies.\n <\/jats:p>\n <\/jats:sec>\n \n Discussion<\/jats:title>\n \n This study expands the mutational spectrum of\n SIAH1<\/jats:italic>\n -associated disorders. We advocate for the inclusion of\n SIAH1<\/jats:italic>\n in diagnostic panels for patients with unexplained neurodevelopmental disorders and multisystem dysmorphisms.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fnins.2025.1677646","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T06:52:25Z","timestamp":1767768745000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A novel variant in SIAH1 associated with autosomal dominant Buratti-Harel syndrome"],"prefix":"10.3389","volume":"19","author":[{"given":"Hong","family":"Zheng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fuwei","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1136\/jmedgenet-2019-106335","article-title":"De novo variants in SIAH1, encoding an E3 ubiquitin ligase, are associated with developmental delay, hypotonia and dysmorphic features.","volume":"58","author":"Buratti","year":"2021","journal-title":"J. Med. Genet."},{"key":"B2","doi-asserted-by":"publisher","first-page":"W306","DOI":"10.1093\/nar\/gki375","article-title":"I-Mutant2.0: Predicting stability changes upon mutation from the protein sequence or structure.","volume":"33","author":"Capriotti","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"i884","DOI":"10.1093\/bioinformatics\/bty560","article-title":"fastp: An ultra-fast all-in-one FASTQ preprocessor.","volume":"34","author":"Chen","year":"2018","journal-title":"Bioinformatics"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e64048","DOI":"10.1002\/ajmg.a.64048","article-title":"Expanding the SIAH1-associated phenotypic spectrum: Insights from loss-of-function variants.","volume":"197","author":"Douiev","year":"2025","journal-title":"Am. J. Med. Genet. 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