Biomarker Landscape in RASopathies

Abstract

RASopathies are a group of related genetic disorders caused by mutations in genes within the RAS/MAPK signaling pathway. This pathway is crucial for cell division, growth, and differentiation, and its disruption can lead to a variety of developmental and health issues. RASopathies present diverse clinical features and pose significant diagnostic and therapeutic challenges. Studying the landscape of biomarkers in RASopathies has the potential to improve both clinical practices and the understanding of these disorders. This review provides an overview of recent discoveries in RASopathy molecular profiling, which extend beyond traditional gene mutation analysis. mRNAs, non-coding RNAs, protein expression patterns, and post-translational modifications characteristic of RASopathy patients within pivotal signaling pathways such as the RAS/MAPK, PI3K/AKT/mTOR, and Rho/ROCK/LIMK2/cofilin pathways are summarized. Additionally, the field of metabolomics holds potential for uncovering metabolic signatures associated with specific RASopathies, which are crucial for developing precision medicine. Beyond molecular markers, we also examine the role of histological characteristics and non-invasive physiological assessments in identifying potential biomarkers, as they provide evidence of the disease's effects on various systems. Here, we synthesize key findings and illuminate promising avenues for future research in RASopathy biomarker discovery, underscoring rigorous validation and clinical translation.

Keywords: RASopathies; biomarkers; molecular signatures; personalized diagnostics; precision medicine.

Figure 1

Molecular biomarkers of RASopathies. (A) Each circle represents a specific RASopathy and includes the associated genes. (B) mRNA detection methods: Overview of the main mRNA detection methods used to study the RASopathies. Created with BioRender.com (accessed on 3 August 2024).

Figure 2

Protein biomarkers of RASopathies. Each color represents a disease: NF1 (blue), LS (gray), CM-AVM (pink), NS (brown), CS (violet), NSML (orange), and CFC (light pink). Inhibitors are indicated in red. Yellow circles denote phosphorylation, and green circles denote ubiquitination. PTM indicates the presence of multiple types of posttranslational modifications on that protein. Created with BioRender.com (accessed on 3 August 2024).

Figure 3

Histological and molecular characterization of RASopathies. Schematic representation of histological (left panel) and molecular (right panel) biomarkers commonly used in RASopathies for diagnosis, prognosis, and treatment response. Created with BioRender.com (accessed on 3 August 2024).

Figure 4

Cardiac, bone, and embryonic RASopathy physiological biomarkers. Each color represents a specific RASopathy. NF1: blue; LS: gray; NS: brown; CS: violet; NSML: orange; CFC: pink. Biomarkers common to all RASopathies are indicated in white. Created with BioRender.com (accessed on 3 August 2024).