Abstract
While individually rare, disorders affecting development collectively represent a substantial clinical, psychological, and socioeconomic burden to patients, families, and society. Insights into the molecular mechanisms underlying these disorders are required to speed up diagnosis, improve counseling, and optimize management toward targeted therapies. Genome sequencing is now unveiling previously unexplored genetic variations in undiagnosed patients, which require functional validation and mechanistic understanding, particularly when dealing with novel nosologic entities. Functional perturbations of key regulators acting on signals’ intersections of evolutionarily conserved pathways in these pathological conditions hinder the fine balance between various developmental inputs governing morphogenesis and homeostasis. However, the distinct mechanisms by which these hubs orchestrate pathways to ensure the developmental coordinates are poorly understood. Integrative functional genomics implementing quantitative in vivo models of embryogenesis with subcellular precision in whole organisms contribute to answering these questions. Here, we review the current knowledge on genes and mechanisms critically involved in developmental syndromes and pediatric cancers, revealed by genomic sequencing and in vivo models such as insects, worms and fish. We focus on the monomeric GTPases of the RAS superfamily and their influence on crucial developmental signals and processes. We next discuss the effectiveness of exponentially growing functional assays employing tractable models to identify regulatory crossroads. Unprecedented sophistications are now possible in zebrafish, i.e., genome editing with single-nucleotide precision, nanoimaging, highly resolved recording of multiple small molecules activity, and simultaneous monitoring of brain circuits and complex behavioral response. These assets permit accurate real-time reporting of dynamic small GTPases-controlled processes in entire organisms, owning the potential to tackle rare disease mechanisms.
Highlights
Rare diseases are individually uncommon but collectively frequent, affecting approximately 25 million people in Europe and impacting between 263 million and 446 million people worldwide (Wakap et al, 2020), with a significant proportion of cases awaiting diagnosis
A large repertoire of genetic conditions described since the discovery of PTPN11 mutations, and more genes and mutations linked to the Ras/MAPK cascade and impacting developmental programs as well as cancer onset continue to be characterized by next-generation sequencing (NGS) and functional genomics efforts (Figure 1, right)
Inactivating mutations of LZTR1 have been associated with drug resistance in RAS-induced chronic myeloid leukemia (Bigenzahn et al, 2018), whereas another class of both loss of function and dominantly acting LZTR1 mutations seems to predispose to the development of glioblastoma and adult-onset schwannomatosis (Piotrowski et al, 2014; Paganini et al, 2015; Motta et al, 2019)
Summary
Rare diseases are individually uncommon but collectively frequent, affecting approximately 25 million people in Europe and impacting between 263 million and 446 million people worldwide (Wakap et al, 2020), with a significant proportion of cases awaiting diagnosis (sources: Orphanet, Eurordis, and WHO, Kaplan et al, 2013). They are often chronic, degenerative, and disabling conditions, which in approximately 70% of cases have a pediatric onset and show high morbidity and mortality. The World Health Organization estimates that half of these tumors are malignant hematological cancers (e.g., leukemia) or solid nervous system tumors (e.g., neuroblastoma) (Gupta et al, 2015; Steliarova-Foucher et al, 2017)
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