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 the 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, truncal hypotonia, laryngomalacia, rocker bottom feet, 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.

MAPK8IP3- related neurodevelopmental disorders are a spectrum of rare conditions caused by de novo mutations in the MAPK8IP3 gene that encodes the JIP3 protein. These disorders are associated with a spectrum of neurodevelopmental symptoms that manifest in children and cause brain abnormalities, profound intellectual disabilities, movement disorders, and developmental delays. JIP3 is required for axonal transport of proteins and organelles between the soma and the synaptic terminal of neurons, a process critical for normal brain development and function. Homozygous loss-of-function mutations in JIP3 lead to impaired axonal transport and aggregation of cargo, which result in axonal swelling and stunted elongation. Despite these severe outcomes, disease mechanisms are poorly understood, and no current treatments are available. Here we conduct thorough morphological, behavioral, and motility phenotyping in the JIP3 knockout zebrafish and identify locomotor deficits and morphological abnormalities. To identify treatment options, we used insights from expert clinicians and the artificial intelligence tool, mediKanren, to identify drug candidates hypothesized to improve patient symptoms or compensate for the loss of JIP3 at the molecular level. We then prioritized drugs that are FDA-approved, safe for children, and readily available. These collective efforts identified amantadine and levodopa as candidate therapies and rescued motor phenotypes associated with JIP3 loss-of-function in zebrafish.

There are over 6,000 different rare diseases estimated to impact 300 million people worldwide. As genetic testing becomes more common practice in the clinical setting, the number of rare disease diagnoses will continue to increase, resulting in the need for novel treatment options. Identifying treatments for these disorders is challenging due to a limited understanding of disease mechanisms, small cohort sizes, interindividual symptom variability, and little commercial incentive to develop new treatments. A promising avenue for treatment is drug repurposing, where FDA-approved drugs are repositioned as novel treatments. However, linking disease mechanisms to drug action can be extraordinarily difficult and requires a depth of knowledge across multiple fields, which is complicated by the rapid pace of biomedical knowledge discovery. To address these challenges, The Hugh Kaul Precision Medicine Institute developed an artificial intelligence tool, mediKanren, that leverages the mechanistic insight of genetic disorders to identify therapeutic options. Using knowledge graphs, mediKanren enables an efficient way to link all relevant literature and databases. This tool has allowed for a scalable process that has been used to help over 500 rare disease families. Here, we provide a description of our process, the advantages of mediKanren, and its impact on rare disease patients.