Introduction: Menke-Hennekam syndrome (MKHK) is an ultra-rare neurodevelopmental disorder first described in 2016 and linked to variants in exons 30-31 of CREBBP and EP300 genes, which are key regulators of chromatin remodeling. Precision genomic diagnosis is essential given MKHK’s clinical heterogeneity. We report a 3-year, 2-month-old male with severe global neurodevelopmental delay, feeding difficulties, failure to thrive, hypodontia, hirsutism, hypertonia, and distinctive facial features, with no relevant family history. His complex presentation underscored the need for individualized molecular investigation to guide prognosis and potential personalized interventions.

Methods: Clinical exome sequencing was performed using the Illumina NextSeq 2000 platform, while Sanger sequencing was used to validate candidate variants. Extensive bioinformatics analysis and a systematic meta-analysis of reported MKHK cases were conducted.

Results: We identified a novel de novo heterozygous variant, NM_004380.3:c.5368T>C p.(Cys1790Arg), in exon 31 of the CREBBP gene, located in the TAZ2 domain. This variant was classified as pathogenic, according to the ACMG 2015 and ACGS 2020 guidelines, using the criteria PM2 (supporting), PM1 (moderate), PP3 (strong) and PS2 (strong). The variant was absent from gnomAD database, located in a mutational hotspot, while in silico predictive tools (including Revel, AlphaMissense, Varity, SIFT, MutationTaster, among others) strongly supported its pathogenicity. Meta-analysis revealed that cysteine substitutions account for over 18% of MKHK cases, particularly clustering within the ZZ and TAZ2 domains.

Conclusions: This finding enriches the personalized genomic understanding of MKHK, emphasizes the diagnostic importance of domain-specific variants, and highlights the utility of early precision diagnosis. Recognizing domain-specific pathogenic mechanisms may enable tailored management strategies and support the development of targeted therapies in the future.