Clinical characterization and genotype–phenotype correlations in Chilton-Okur-Chung syndrome

Year: 2026

Type: article

Abstract: Chilton-Okur-Chung neurodevelopmental syndrome is a rare disorder characterized by global developmental delay, variable intellectual disability, behavioral challenges, and structural brain anomalies caused by variants in CDC42BPB . CDC42BPB encodes MRCKβ, a ubiquitously expressed serine/threonine kinase involved in cytoskeletal regulation. The phenotypic spectrum and genotype–phenotype relationships remain incompletely characterized. We aggregated data from 20 newly identified individuals and 17 previously reported individuals. We analyzed the data for genotype–phenotype correlations according to variant type. Developmental delay was the most common phenotype, affecting 85% of individuals, with early delays notable in walking and speech. Intellectual disability was observed in 62%. Behavioral diagnoses included autism spectrum disorder (68%) and ADHD (60%). Structural brain abnormalities were present in 48% of cases, predominantly affecting the cerebellum and ventricles. Dysmorphic features were present in 83% of cases. Hypotonia was present in 68%, seizures in 41%, and macrocephaly in 38%. Genotype–phenotype analysis indicated that predicted loss-of-function (LoF) variants were generally associated with milder neurodevelopmental features than missense variants. A male predominance was observed despite this being an autosomal dominant condition, suggesting a possible protective effect in females. Some heterozygous predicted LoF variants were inherited from self-reported unaffected parents or with subtle neurodevelopmental or cardiac features, supporting incomplete penetrance and variable expressivity. Our findings highlight the differences between predicted loss-of-function and missense variants. Future studies assessing biochemical differences in kinase activity and substrate specificity may explain these clinical differences.

Source: BMC Medical Genomics

Institutions: Boston Children's Hospital, Harvard University, Universitat Autònoma de Barcelona, Vall d'Hebron Institut de Recerca, Vall d'Hebron Hospital Universitari, Hunter Genetics, Hunter New England Local Health District, Oftalmología Vistahermosa SL, Leiden University Medical Center, UNSW Sydney, Sydney Children's Hospital, Sydney Children’s Hospitals Network, University of Manchester, Manchester University NHS Foundation Trust, Health Innovation Manchester, Pennsylvania State University, University Medical Center Groningen, University of Groningen, University of Newcastle Australia, Instituto de Salud Carlos III, Hospital de Sant Pau, Centre for Biomedical Network Research on Rare Diseases, Institut de Recerca Sant Pau, Garvan Institute of Medical Research, University of Calgary, Alberta Children's Hospital, Texas Christian University, Cook Children's Medical Center, Miami Children's Hospital

Language: English

Topic: Genetics and Neurodevelopmental Disorders

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,190

Funder: Intellectual and Developmental Disabilities Research Center

Award: G3830015915

OpenAlex ID: W7203476236