De novo missense variants in CHTF18: The potential to expand the clinical spectrum of cohesinopathies.

Cohesin is a multiprotein complex that maintains chromosome integrity during cell division. Disruptions in cohesin or its regulators, including CHTF18, can lead to neurodevelopmental and congenital disorders known as cohesinopathies. CHTF18 participates in cohesin loading during DNA replication, but its role in human disease is not understood. Through exome analysis of >665,000 individuals, we identified multiple (<10) unrelated individuals with rare missense variants in CHTF18 and overlapping clinical phenotypes suggestive of a cohesinopathy disorder. Among these, three individuals with neurodevelopmental delay and epilepsy, each carrying a previously unreported rare de novo variant in CHTF18, are presented in detail. Overlapping clinical features of additional individuals who were not available for case-level consent are presented in aggregate. All the CHTF18 variants in the cohort were located in the vicinity of the AAA+ATPase domain of CHTF18, which plays a crucial role in cohesin loading during DNA replication. In addition to cohort findings from our large database, the function, relevance, and pathway involvement of CHTF18 make it a promising candidate gene for disease. The study calls for further research to explore the role of CHTF18 variants in disease and highlights the importance of including CHTF18 as a candidate gene in broad genetic testing for individuals with unsolved neurodevelopmental conditions.