Exploring a Mechanism-Based Therapeutic Approach for ZC4H2 Haploinsufficiency

This report explores a therapeutic hypothesis for addressing the potential effects of a loss-of-function variant in the ZC4H2 gene. We describe a pediatric female (born 2020) with developmental delay associated with an early truncation variant in ZC4H2. This genetic alteration is suspected to reduce levels of functional ZC4H2 protein (encoded by the ZC4H2 gene). Variants in ZC4H2 are associated with Wieacker-Wolff and Miles-Carpenter Syndrome, which are characterized by intellectual disability, developmental delay, congenital contractures, and seizures. The patient presents with multiple developmental manifestations, including developmental delay, intellectual disability, joint contractures and dislocations, coronal craniosynostosis, atrial septal defect, truncal hypotonia, laryngomalacia, rocker bottom feet, widely spaced nipples, and intermittent esotropia. We hypothesize that targeting the downstream effects of ZC4H2 haploinsufficiency, such as synaptic dysfunction and impaired dendritic spine stability, may help mitigate the patient’s symptoms by restoring synaptic homeostasis. This report outlines the rationale for this therapeutic hypothesis, which is informed by genetic findings, prior literature, and recent mechanistic insights. Further studies are needed to validate underlying disease mechanisms and to evaluate the candidate therapy for safety and efficacy.