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

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.

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Journal
BMC Medical Genomics
Published
2026-08-14
DOI
https://doi.org/10.1186/s12920-026-02448-w
Primary Topic
Neurogenetic and Muscular Disorders Research
Type
article
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article

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

Jelmer Legebeke, Ermal Aliu, Nicolette S. den Hollander, Anna M. Cueto‐González et al.
BMC Medical Genomics
Neurogenetic and Muscular Disorders Research
article

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

Jelmer Legebeke, Ermal Aliu, Nicolette S. den Hollander, Anna M. Cueto‐González, Mehmet Buğrahan Düz, Amaia Lasa‐Aranzasti, Ivon Cusco Marti, Jolien S. Klein Wassink‐Ruiter, Ana Cazurro‐Gutiérrez, Ela Curic, Dr Marta Codina-Solà, Anna Hackett, Ryan Gates, Arthur Arenas Périco, David Gómez-Andrés, Lisa Ewans, Shane McKee, Susan Sell, Sajel Lala Kana, Elizabeth A. Jones, Himanshu Goel, Núria Martínez-Gil, Elizabeth Emma Palmer, Siddharth Banka, Mary Ann Thomas, Wendy K. Chung, Hermine E. Veenstra-Knol, Claudia A. L. Ruivenkamp
article en

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.

BMC Medical Genomics
Hebron University (PS), Universitat Autònoma de Barcelona (ES), Universidade Estadual de Maringá (BR), Boston Children's Hospital (US), Texas Christian University (US), New South Wales Department of Health (AU), University Medical Center Groningen (NL), Harvard University (US), Garvan Institute of Medical Research (AU), University of Groningen (NL), Leiden University Medical Center (NL), Instituto de Salud Carlos III (ES), Hospital de Sant Pau (ES), Alberta Children's Hospital (CA), University of Manchester (GB), Cook Children's Medical Center (US), Manchester University NHS Foundation Trust (GB), Hunter Genetics (AU), Vall d'Hebron Institut de Recerca (ES), Nemours Children's Health System (US), Centre for Biomedical Network Research on Rare Diseases (ES), Golisano Children's Hospital (US), Sydney Children's Hospital (AU), Health Innovation Manchester (GB), Vall d'Hebron Hospital Universitari (ES), Miami Children's Hospital (US), Sydney Children’s Hospitals Network (AU), Instituto de Investigación de Enfermedades Raras (ES), University of Newcastle Australia (AU), Penn State Milton S. Hershey Medical Center (US)
Intellectual and Developmental Disabilities Research Center
Openalex Percentile: Top 10%
Neurogenetic and Muscular Disorders Research
DOIOpen Access PDFOpenAlex
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