Molecular mechanisms of human overgrowth and use of omics in its diagnostics: chances and challenges

Abstract

Overgrowth disorders comprise a group of entities with a variable phenotypic spectrum ranging from tall stature to isolated or lateralized overgrowth of body parts and or organs. Depending on the underlying physiological pathway affected by pathogenic genetic alterations, overgrowth syndromes are associated with a broad spectrum of neoplasia predisposition, (cardio) vascular and neurodevelopmental anomalies, and dysmorphisms. Pathologic overgrowth may be of prenatal or postnatal onset. It either results from an increased number of cells (intrinsic cellular hyperplasia), hypertrophy of the normal number of cells, an increase in interstitial spaces, or from a combination of all of these. The underlying molecular causes comprise a growing number of genetic alterations affecting skeletal growth and Growth-relevant signaling cascades as major effectors, and they can affect the whole body or parts of it (mosaicism). Furthermore, epigenetic modifications play a critical role in the manifestation of some overgrowth diseases. The diagnosis of overgrowth syndromes as the prerequisite of a personalized clinical management can be challenging, due to their clinical and molecular heterogeneity. Physicians should consider molecular genetic testing as a first diagnostic step in overgrowth syndromes. In particular, the urgent need for a precise diagnosis in tumor predisposition syndromes has to be taken into account as the basis for an early monitoring and therapy. With the (future) implementation of next-generation sequencing approaches and further omic technologies, clinical diagnoses can not only be verified, but they also confirm the clinical and molecular spectrum of overgrowth disorders, including unexpected findings and identification of atypical cases. However, the limitations of the applied assays have to be considered, for each of the disorders of interest, the spectrum of possible types of genomic variants has to be considered as they might require different methodological strategies. Additionally, the integration of artificial intelligence (AI) in diagnostic workflows significantly contribute to the phenotype-driven selection and interpretation of molecular and physiological data.

Keywords: diagnostics; long read sequencing; massive parallel sequencing (MPS); mosaicism; omics; overgrowth.

FIGURE 1

Molecular pathways for somatic growth and causative effectors for overgrowth entities. The cellular localization of the relevant gene products is roughly presented relative to the nuclear- and outer cell-membranes. Arrows depict activating, bars illustrate blocking signaling effects between two molecules. Kinked arrows illustrate transcription of a depicted gene. Circles illustrate functional multiprotein complexes. Overgrowth syndromes are listed with their abbreviations at the sites of their causative effect (i.e., mutations in the gene linked to the disease). (”?” indicates that the effect between two molecules has not been functionally described yet. For disease abbreviations see Table 1).

FIGURE 2

Current and emerging Omics techniques and their usage in the diagnostic flow-chart for rare overgrowth syndromes. The diagram depicts the different omics fields (genomics, epigenetics, transcriptomics and proteomics) currently used to address diagnostic aspects of overgrowth entities that follow the medical anamnesis. Selection of the most promising diagnostic approach can be assisted by AI based techniques like Face2Gene (compare main text). Methods listed are not complete, but focus on the most prominent ones.