miRNA biogenesis and inherited disorders: clinico-molecular insights

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• MicroRNAs (miRNAs) are crucial regulators of gene expression via miRNA-induced gene silencing.
• The biogenesis of miRNAs involves key genes such as DROSHA, DGCR8, DICER1, and AGO1/2.
• Germline pathogenic variants (GPVs) in these miRNA biogenesis genes are associated with distinct genetic syndromes.

Purpose of the Study:

• To provide an updated overview of how GPVs in miRNA biogenesis genes impact miRNA biology.
• To elucidate the clinical manifestations resulting from alterations in miRNA biogenesis pathways.
• To consolidate recent findings on DICER1, DGCR8, AGO1, and AGO2 GPVs.

Main Methods:

• Literature review and synthesis of recent research findings.
• Analysis of genotype-phenotype correlations in patients with GPVs in miRNA biogenesis genes.
• Review of molecular mechanisms underlying miRNA dysregulation in genetic syndromes.

Main Results:

• GPVs in DICER1 are linked to tumor predisposition.
• GPVs in DGCR8, AGO1, and AGO2 have emerging clinical consequences, including neurodevelopmental disorders (NDDs).
• Alterations in miRNA biogenesis genes lead to a spectrum of clinical phenotypes.

Conclusions:

• GPVs in miRNA biogenesis genes disrupt normal miRNA function.
• These disruptions result in diverse genetic syndromes with varied clinical outcomes, including NDDs and neoplastic conditions.
• Understanding these pathways is critical for diagnosing and managing affected individuals.