Novel SEMA3E Frameshift Variant Linked to CHARGE-Like Features in Child

A one-year-old boy with developmental delay, microcephaly and kidney malformations has been found to carry a previously unreported de novo mutation in the SEMA3E gene, according to a case study published in BMC Medical Genomics on 4 November 2026. The variant, identified through trio whole exome sequencing of the child and his parents, adds new evidence that SEMA3E may be a candidate gene for CHARGE syndrome, a rare genetic condition whose molecular basis remains incompletely understood.

The child was evaluated after clinicians suspected CHARGE syndrome, a recognizable genetic disorder defined by a pattern of multiple organ malformations. His clinical presentation included global developmental delay, microcephaly, widely spaced eyes, low-set ears, auricular malformation, bilateral renal hypoplasia and gastroesophageal reflux. To search for a genetic explanation, the research team collected all of his clinical data and performed whole exome sequencing on the patient and both parents, followed by Sanger sequencing to confirm the finding.

That analysis revealed a de novo heterozygous variant, meaning it appeared in the child but was absent from both parents. The mutation, written as SEMA3E c.1983_1984insCTTT, inserts four DNA letters into the gene’s coding sequence. Database searches confirmed it had not been documented in SNP databases, marking it as novel. Because it arose in the child rather than being inherited, the finding points to a spontaneous mutation event during formation of the egg, sperm or early embryo.

The insertion has a disruptive consequence at the protein level. Bioinformatics analysis predicts that the frameshift mutation terminates the protein at codon 668, producing a truncated SEMA3E protein with approximately 88 amino acid residues missing at its C-terminus. Critically, the truncation falls within the disulfide-bond domain, which spans residues 654 to 729 of the SEMA3E protein. This domain is structurally important, and losing part of it is predicted to impair the protein’s normal function.

SEMA3E encodes a member of the semaphorin family of signaling proteins, molecules best known for guiding nerve cell development. The link between SEMA3E and CHARGE syndrome has not been well understood, which is precisely why this single case carries weight. The study’s authors conclude that the novel, likely pathogenic variant identified in their patient provides evidence that SEMA3E is a candidate gene for the condition. In genetic medicine, a candidate gene is one suspected of contributing to a disease based on evidence from affected individuals, but which has not yet been firmly established as a definitive cause.

Beyond the genetic finding, the researchers also conducted an exploratory non-targeted metabolomics analysis, reported in the supplementary materials, which revealed differences in the patient’s metabolic profile compared with that of his parents. The team is careful about the interpretation, however. Due to limitations related to the single-subject nature of the study and confounding factors, they state these results cannot yet serve as mechanistic evidence supporting a SEMA3E-related pathogenesis and should be considered only as a hypothesis for future research.

That caution reflects a broader reality in rare disease genetics. Case reports of individual patients are often the first signal that a gene is involved in a syndrome, but a single patient cannot establish causation on its own. Variants must be assessed for pathogenicity using standardized criteria, and the biological plausibility of the mechanism matters. Here, the fact that the mutation is de novo, absent from population databases and predicted to truncate the protein within a functional domain all strengthen the argument that it contributes to the child’s condition.

The study also illustrates the diagnostic power of trio whole exome sequencing, in which the affected child and both parents are sequenced together. Comparing the child’s genome against those of the parents allows clinicians to distinguish inherited variants from spontaneous ones, a distinction that is central to interpreting whether a mutation explains a patient’s symptoms. Confirmation by Sanger sequencing, an older but highly accurate method, remains standard practice for validating variants discovered by exome sequencing before they are reported to families.

For families affected by CHARGE syndrome and related conditions, each newly identified candidate gene expands the map of possible genetic causes, which can eventually improve diagnosis and genetic counseling. The authors of this study emphasize that their finding is a single case, and further research will be needed to confirm SEMA3E’s role and to understand how disruptions to the gene produce the constellation of malformations seen in this child. The metabolomics data, while preliminary, may offer a starting point for that future work.

Subject of Research: A novel de novo SEMA3E frameshift variant identified in a child with a CHARGE-like phenotype

Article Title: A de novo SEMA3E frameshift variant in a child with CHARGE-like phenotype

Article References: Xiao, Y., Gao, Y., Chen, J., Lei, Y., Liang, J., Qiao, L., Zuo, L., Zhu, H., & Wang, J. (2026). A de novo SEMA3E frameshift variant in a child with CHARGE-like phenotype. BMC Medical Genomics. https://doi.org/10.1186/s12920-026-02494-4

Image Credits: AI Generated

DOI: 10.1186/s12920-026-02494-4

Keywords: SEMA3E, CHARGE syndrome, frameshift variant, de novo mutation, whole exome sequencing, truncated protein, disulfide-bond domain, global developmental delay, microcephaly, renal hypoplasia, candidate gene, metabolomics