Case Report: Identification of a de novo missense variant in the N-terminal zinc-finger domain of ZEB2 in a patient presenting with neurodevelopmental delay and recurrent pulmonary infections.

BACKGROUND: Heterozygous variants in the ZEB2 gene are known to cause Mowat-Wilson syndrome (MWS). The classical clinical spectrum of MWS includes characteristic facial features, intellectual disability, epilepsy, Hirschsprung disease (HSCR), and various congenital malformations. Reported pathogenic variants have predominantly been truncating variants or missense variants involving the C-terminal zinc-finger domain. To date, no disease-causing missense variant affecting the N-terminal zinc-finger domain has been documented.

CASE PRESENTATION: We report a 3-year-old boy presenting with characteristic facial features, global developmental delay, and recurrent respiratory tract infections. Trio-based exome sequencing identified a de novo heterozygous missense variant in ZEB2, c.652C>T (p. Arg218Trp), located within the N-terminal zinc-finger domain. The patient exhibited a phenotype distinct from classical MWS, characterized by atypical facial dysmorphisms (including an elongated face, midface hypoplasia/depression, frontal bossing, esotropia, and hypertelorism), global developmental delay, and recurrent respiratory infections. Following comprehensive rehabilitation therapy (motor, cognitive, and language training) combined with oral zinc supplementation (elemental zinc 5 mg/day, approximately 0.3 mg/kg), the patient showed a marked reduction in respiratory infections and normalization of immune parameters after 12 months of treatment.

CONCLUSION: This report describes a patient with a de novo missense variant in the N-terminal zinc-finger domain of ZEB2 who presented with neurodevelopmental delay, atypical facial features, and recurrent respiratory infections, alongside a reduction in infection frequency during zinc supplementation. The variant is classified as likely pathogenic, and these observations expand the phenotypic variability potentially associated with ZEB2 variants. Additional cases and functional studies are required to confirm any causal link between the variant, the observed phenotype, and the effects of zinc supplementation.