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A labor-induced fetus presenting with classical CHARGE features was found to carry a de novo heterozygous missense variant in SEMA3E, c.1327G>A (p.Ala443Thr), by whole-exome sequencing followed by Sanger validation (PMID:31691538). This variant was absent in parental samples and cosegregated fully with the phenotype in the single family assessed. The substitution lies within the conserved Sema domain and is predicted deleterious by multiple in silico tools, supporting a disruption of SEMA3E-mediated axon guidance during development. No additional unrelated probands or families with SEMA3E variants in CHARGE syndrome have been reported. Functional data specific to CHARGE are lacking, although SEMA3E’s established role in neural crest and cranial nerve development provides mechanistic plausibility. Taken together, current evidence supports a limited association between SEMA3E and CHARGE syndrome, warranting further study in larger cohorts.
Gene–Disease AssociationLimitedSingle proband ([PMID:31691538]) with de novo SEMA3E variant; no additional families or replication Genetic EvidenceLimitedOne de novo heterozygous missense variant cosegregating with CHARGE phenotype ([PMID:31691538]) Functional EvidenceLimitedVariant located in conserved Sema domain with in silico deleterious prediction; no direct functional assays in CHARGE context |