# The Phenotype-Based Approach Can Solve Cold Cases: The Paradigm of Mosaic Mutations of the CREBBP Gene

## TL;DR

This paper presents a case of Rubinstein–Taybi syndrome with a rare mosaic mutation in the CREBBP gene and suggests that combining phenotype-based diagnosis with advanced sequencing can improve detection of mild or mosaic cases.

## Contribution

The study reports the first clinical case of RTS with a mosaic CREBBP truncating variant and advocates for a phenotype-based approach combined with high-depth NGS for better diagnosis.

## Key findings

- A patient with RTS was found to have a mosaic CREBBP truncating variant, the first such case reported.
- Applying clinical diagnostic guidelines to CREBBP mosaicism cases confirmed the high specificity of the consensus criteria.
- The study suggests that milder RTS cases may be underdiagnosed and that targeted approaches can improve diagnostic yield.

## Abstract

Rubinstein–Taybi syndrome (RTS) is a rare genetic disorder characterized by intellectual disability, facial dysmorphisms, and enlarged thumbs and halluces. Approximately 55% of RTS cases result from pathogenic variants in the CREBBP gene, with an additional 8% linked to the EP300 gene. Given the close relationship between these two genes and their involvement in epigenomic modulation, RTS is grouped into chromatinopathies. The extensive clinical heterogeneity observed in RTS, coupled with the growing number of disorders involving the epigenetic machinery, poses a challenge to a phenotype-based diagnostic approach for these conditions. Here, we describe the first case of a patient clinically diagnosed with RTS with a CREBBP truncating variant in mosaic form. We also review previously described cases of mosaicism in CREBBP and apply clinical diagnostic guidelines to these patients, confirming the good specificity of the consensus. Nonetheless, these reports raise questions about the potential underdiagnosis of milder cases of RTS. The application of a targeted phenotype-based approach, coupled with high-depth NGS, may enhance the diagnostic yield of whole-exome sequencing (WES) in mild and mosaic conditions.