Abstract:

Objective To analyze the clinical characteristics of children carrying truncating variants in the last exon of CREBBP and to explore their phenotypic features in comparison with the classical Rubinstein-Taybi syndrome (RSTS). Methods The clinical and genetic data of three patients carrying truncating variants in the last exon of CREBBP (NM_004380.3) were retrospectively reviewed. Their phenotypic features were compared with previously reported cases involving last exon variants and with the classical RSTS phenotype. Results All three patients harbored heterozygous nonsense variants in the last exon of CREBBP. All three variants arose de novo. Two variants had been previously reported, and one was novel. According to ACMG/AMP guidelines, the variants were classified as pathogenic or likely pathogenic. All patients exhibited features within the RSTS spectrum, while the core manifestations varied. One patient showed broad thumbs/halluces and several characteristic facial features of RSTS, whereas the other two displayed only partial RSTS-related features and did not fully meet the classical phenotype. A review of the literature indicated that patients with CREBBP last exon variants demonstrated heterogeneity in the expression of core features and disease severity. Conclusions Patients with nonsense variants in the last exon of CREBBP generally fall within the RSTS phenotypic spectrum, although their clinical manifestations may be atypical or incomplete. Comprehensive evaluation integrating detailed phenotypic assessment with molecular findings is important for accurate diagnosis and genetic counseling.

Key words: CREBBP, Rubinstein-Taybi syndrome, nonsense variant, last exon, phenotypic heterogeneity