A Novel Intragenic Duplication of CREBBP in Rubinstein-Taybi Syndrome: A Case Report Expanding the Genotype-Phenotype Spectrum.

Abstract

Introduction: Rubinstein-Taybi syndrome (RSTS) is most often caused by loss-of-function variants in CREBBP; intragenic duplications are rare and extremely under-recognized.

Case presentation: We describe a 5-year-old girl with global developmental delay, intellectual disability, frontal bossing, upslanted palpebral fissures, broad angulated halluces, and scoliosis. Whole-exome sequencing with copy number analysis revealed a heterozygous de novo duplication of approximately 13 kb encompassing exons 7-16 of CREBBP (NM_004380.3). Multiplex ligation-dependent probe amplification confirmed the duplication in the proband and excluded it in both parents. The event is predicted to introduce a frameshift, leading to premature truncation. No additional pathogenic variants were detected.

Conclusion: This is the first reported CREBBP duplication spanning exons 7-16, expanding the mutational spectrum of RSTS and illustrating that intragenic duplications can manifest with a partially atypical craniofacial profile. The case underscores the value of incorporating high-resolution copy number interrogation into RSTS workflows when single nucleotide variant analysis is uninformative and supports systematic deposition of such variants to refine genotype-phenotype correlations.