Submission Details

CDC42 was first reported in relation to autosomal dominant macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome (sometimes known as Takenouchi-Kosaki syndrome) in 2015 (Takenouchi T, et al., 2015, PMID: 26386261). CDC42, a master regulator of actin cytoskeleton and major node in intracellular signaling, is associated with a heterogeneous set of developmental and multi-system phenotypes, demonstrating the critical requirement of proper CDC42 function in a large array of developmental processes. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Patients have a broad spectrum of anomalies; core clinical features include defective growth, intellectual disability, facial dysmorphism, hearing/vision problems, cardiac malformations, immune, hematologic, and lymphatic abnormalities, and brain malformations. Nine unique missense variants have been reported in this gene in at least 9 probands in 2 publications (PMIDs: 26386261 and 29394990). Segregation was observed in one family (Family 30153 in PMID: 29394990), all others were de novo occurrences. This gene-disease relationship is supported by its interaction with WAS (PMID: 8643625) and multiple model systems with partial recapitulation of human disease (PMIDs: 29394990, 16510873, 20139097, 22387309). In summary CDC42 is definitively associated with autosomal dominant macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome.