miRNA biogenesis and inherited disorders: clinico-molecular insights

MicroRNAs (miRNAs) play vital roles in the regulation of gene expression, a process known as miRNA-induced gene silencing. The human genome codes for many miRNAs, and their biogenesis relies on a handful of genes, including DROSHA, DGCR8, DICER1, and AGO1/2. Germline pathogenic variants (GPVs) in these genes cause at least three distinct genetic syndromes, with clinical manifestations that range from hyperplastic/neoplastic entities to neurodevelopmental disorders (NDDs). Over the past decade, DICER1 GPVs have been shown to lead to tumor predisposition. Moreover, recent findings have provided insight into the clinical consequences arising from GPVs in DGCR8, AGO1, and AGO2. Here we provide a timely update with respect to how GPVs in miRNA biogenesis genes alter miRNA biology and ultimately lead to their clinical manifestations.

Automated summary

MicroRNAs (miRNAs) are crucial for gene expression regulation, and their biogenesis depends on specific genes such as DROSHA, DGCR8, DICER1, and AGO1/2. Germline pathogenic variants (GPVs) in these genes lead to different genetic syndromes with diverse clinical manifestations. DICER1 GPVs are associated with tumor predisposition, while recent studies have shed light on the clinical consequences of GPVs in DGCR8, AGO1, and AGO2. This review provides an up-to-date summary on how GPVs in miRNA biogenesis genes affect miRNA biology and contribute to clinical manifestations.