Identification of a novel, pathogenic CREBBP variant in a patient with Menke-Hennekam syndrome: a Case Report
Menke-Hennekam syndrome (MKHK) is a recently described rare autosomal dominant disorder caused by loss-of-function variants in exon 30 or 31 of CREBBP (CREB-binding protein) or EP300 genes. These genes encode transcriptional coactivators with a key role in chromatin remodeling and regulation of gene...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2025.1585453/full |
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| author | Anna Μaria Anastasiou Anna Μaria Anastasiou Constantia Aristidou Athina Theodosiou Ludmila Kousoulidou Ioannis Papaevripidou Angelos Alexandrou Paola Evangelidou Carolina Sismani George A. Tanteles George A. Tanteles Despina Sanoudou Despina Sanoudou Aristides G. Eliopoulos Aristides G. Eliopoulos |
| author_facet | Anna Μaria Anastasiou Anna Μaria Anastasiou Constantia Aristidou Athina Theodosiou Ludmila Kousoulidou Ioannis Papaevripidou Angelos Alexandrou Paola Evangelidou Carolina Sismani George A. Tanteles George A. Tanteles Despina Sanoudou Despina Sanoudou Aristides G. Eliopoulos Aristides G. Eliopoulos |
| author_sort | Anna Μaria Anastasiou |
| collection | DOAJ |
| description | Menke-Hennekam syndrome (MKHK) is a recently described rare autosomal dominant disorder caused by loss-of-function variants in exon 30 or 31 of CREBBP (CREB-binding protein) or EP300 genes. These genes encode transcriptional coactivators with a key role in chromatin remodeling and regulation of gene expression. Herein, we report the identification and characterization of a novel missense variant in CREBBP, NM_004380.3:c.5368T>C p.(Cys1790Arg), in a 4-year-old male. The clinical presentation of the patient included global developmental delay, intellectual disability, growth retardation, and distinct craniofacial dysmorphisms, resembling known MKHK subtypes, but also exhibiting less common or unique features such as excessive palmar skin and the absence of recurrent infections and autism spectrum behaviors. Genetic analysis via trio-based clinical exome sequencing confirmed the de novo origin of the CREBBP variant, which was classified as pathogenic based on ACGS guidelines 2020. Structural modeling predicted that the NP_004371.2:p.(Cys1790Arg) substitution may disrupt the tertiary structure of the CBP TAZ2 domain (amino acids 1772-1840) when interacting with STAT1 but not with adenovirus E1A, potentially affecting transcription factor binding and disease phenotype. The findings contribute to the evolving classification of MKHK subtypes and to deciphering the complexity of genotype-phenotype relationships in MKHK. |
| format | Article |
| id | doaj-art-43138d41f09c47c682a95c28c984abf6 |
| institution | Kabale University |
| issn | 1664-8021 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj-art-43138d41f09c47c682a95c28c984abf62025-08-20T04:02:27ZengFrontiers Media S.A.Frontiers in Genetics1664-80212025-08-011610.3389/fgene.2025.15854531585453Identification of a novel, pathogenic CREBBP variant in a patient with Menke-Hennekam syndrome: a Case ReportAnna Μaria Anastasiou0Anna Μaria Anastasiou1Constantia Aristidou2Athina Theodosiou3Ludmila Kousoulidou4Ioannis Papaevripidou5Angelos Alexandrou6Paola Evangelidou7Carolina Sismani8George A. Tanteles9George A. Tanteles10Despina Sanoudou11Despina Sanoudou12Aristides G. Eliopoulos13Aristides G. Eliopoulos14Department of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, GreeceClinical Genomics and Pharmacogenomics Unit, 4th Pathology Clinic, School of Medicine, National and Kapodistrian University of Athens, Athens, GreeceDepartment of Clinical Genetics and Genomics, The Cyprus Institute of Neurology and Genetics, Nicosia, CyprusDepartment of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, Nicosia, CyprusDepartment of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, Nicosia, CyprusDepartment of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, Nicosia, CyprusDepartment of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, Nicosia, CyprusDepartment of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, Nicosia, CyprusDepartment of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, Nicosia, CyprusDepartment of Clinical Genetics and Genomics, The Cyprus Institute of Neurology and Genetics, Nicosia, CyprusDepartment of Basic and Clinical Sciences, University of Nicosia Medical School, Nicosia, CyprusClinical Genomics and Pharmacogenomics Unit, 4th Pathology Clinic, School of Medicine, National and Kapodistrian University of Athens, Athens, GreeceCenter of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, GreeceDepartment of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, GreeceGenosophy S.A., National and Kapodistrian University of Athens spin-off company, Athens, GreeceMenke-Hennekam syndrome (MKHK) is a recently described rare autosomal dominant disorder caused by loss-of-function variants in exon 30 or 31 of CREBBP (CREB-binding protein) or EP300 genes. These genes encode transcriptional coactivators with a key role in chromatin remodeling and regulation of gene expression. Herein, we report the identification and characterization of a novel missense variant in CREBBP, NM_004380.3:c.5368T>C p.(Cys1790Arg), in a 4-year-old male. The clinical presentation of the patient included global developmental delay, intellectual disability, growth retardation, and distinct craniofacial dysmorphisms, resembling known MKHK subtypes, but also exhibiting less common or unique features such as excessive palmar skin and the absence of recurrent infections and autism spectrum behaviors. Genetic analysis via trio-based clinical exome sequencing confirmed the de novo origin of the CREBBP variant, which was classified as pathogenic based on ACGS guidelines 2020. Structural modeling predicted that the NP_004371.2:p.(Cys1790Arg) substitution may disrupt the tertiary structure of the CBP TAZ2 domain (amino acids 1772-1840) when interacting with STAT1 but not with adenovirus E1A, potentially affecting transcription factor binding and disease phenotype. The findings contribute to the evolving classification of MKHK subtypes and to deciphering the complexity of genotype-phenotype relationships in MKHK.https://www.frontiersin.org/articles/10.3389/fgene.2025.1585453/fullMenke-Hennekam syndromeCREBBPgeneticscase reportvariantRubinstein-Taybi syndrome |
| spellingShingle | Anna Μaria Anastasiou Anna Μaria Anastasiou Constantia Aristidou Athina Theodosiou Ludmila Kousoulidou Ioannis Papaevripidou Angelos Alexandrou Paola Evangelidou Carolina Sismani George A. Tanteles George A. Tanteles Despina Sanoudou Despina Sanoudou Aristides G. Eliopoulos Aristides G. Eliopoulos Identification of a novel, pathogenic CREBBP variant in a patient with Menke-Hennekam syndrome: a Case Report Frontiers in Genetics Menke-Hennekam syndrome CREBBP genetics case report variant Rubinstein-Taybi syndrome |
| title | Identification of a novel, pathogenic CREBBP variant in a patient with Menke-Hennekam syndrome: a Case Report |
| title_full | Identification of a novel, pathogenic CREBBP variant in a patient with Menke-Hennekam syndrome: a Case Report |
| title_fullStr | Identification of a novel, pathogenic CREBBP variant in a patient with Menke-Hennekam syndrome: a Case Report |
| title_full_unstemmed | Identification of a novel, pathogenic CREBBP variant in a patient with Menke-Hennekam syndrome: a Case Report |
| title_short | Identification of a novel, pathogenic CREBBP variant in a patient with Menke-Hennekam syndrome: a Case Report |
| title_sort | identification of a novel pathogenic crebbp variant in a patient with menke hennekam syndrome a case report |
| topic | Menke-Hennekam syndrome CREBBP genetics case report variant Rubinstein-Taybi syndrome |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2025.1585453/full |
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