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

CHARGE syndrome (CS) is a recognizable genetic syndrome with known pattern of multiple organ malformations and the association between SEMA3E and CS is not well understood. In a one-year-old boy who suspected diagnosis with CS, all his clinical data were collected and trio whole exome sequencing (WES) and Sanger sequencing were performed in the patient and his parents for genetic tests. The patient had global developmental delay, microcephaly, hypertelorism, low-set ears, auricular malformation, bilateral renal hypoplasia, and gastroesophageal reflux. A de novo heterozygous SEMA3E c.1983_1984insCTTT was found in the patient and it was not documented in SNP databases. Bioinformatics analysis predicts that this frameshift mutation terminates at codon 668, resulting in the production of a truncated protein with approximately 88 amino acid residues missing at the C-terminus; this truncation occurs within the disulfide-bond domain (residues 654–729) of the SEMA3E protein. In addition, exploratory non-targeted metabolomics analysis (Supplementary Materials) revealed differences in the patient’s metabolic profile compared to that of his parents; however, due to limitations related to the single-subject nature of the study and confounding factors, these results cannot yet serve as mechanistic evidence supporting a SEMA3E -related pathogenesis and should be considered only as a hypothesis for future research. A novel, likely pathogenic variant identified in this study provides evidence that SEMA3E is a candidate gene for CHARGE syndrome.