Complex congenital cardiovascular anomaly in a patient with AGO1‐associated disorder

Abstract

Pathogenic AGO1 variants have been associated with neurodevelopmental disorders, including autism spectrum disorder, developmental delay, intellectual disability, and dysmorphic facial appearance. In mammalian models, defects in microRNA (miRNA) biogenesis are associated with congenital heart disease and dilated cardiomyopathy. We describe the case of a patient with partial anomalous pulmonary venous return, hypoplastic left lung, bilateral pulmonary sequestration, and dilated myocardiopathy. We identified a de novo pathogenic variant of AGO1, which encodes an Argonaute protein forming a gene-silencing complex with microRNAs.The patient was diagnosed with dilated cardiomyopathy with no apparent cause at 3 years of age. She was started on enalapril and carvedilol, and her heart failure was well controlled. We expanded the AGO1-associated phenotype to include complex congenital cardiovascular anomaly and dilated cardiomyopathy in humans.

Extracellular Vesicle microRNAs in Heart Failure: Pathophysiological Mediators and Therapeutic Targets

“…miRNA biogenesis is tightly controlled at all levels including transcription, processing, modification and Argonaute (AGO) protein loading as well as RNA decay [22]. Increasing evidence supports the view that dysregulation of miRNA biogenesis is associated with human HF [23][24][25][26]. miRNA biogenesis can be regulated either by the canonical pathway (Figure 1A) or non-canonical pathways (Figure 1B,C,E).…”

Extracellular Vesicle MicroRNAs in Heart Failure: Pathophysiological Mediators and Therapeutic Targets

“…miRNA biogenesis is tightly controlled at all levels, including transcription, processing, modification, and Argonaute (AGO) protein loading as well as RNA decay [22]. Increasing evidence supports the view that dysregulation of miRNA biogenesis is associated with human HF [23][24][25][26]. miRNA biogenesis can be regulated either by the canonical pathway (Figure 1-I) or non-canonical pathways (Figure 1-II, III, V).…”

Modeling neurodevelopmental disorder-associatedhAGO1mutations inC. elegansArgonauteALG-1

“…It is striking that the reported hAGO1 and hAGO2 NDD mutations are mostly single amino acid changes [20][21][22]. The rarity of frameshift, truncation, or large deletions suggests that singlegene hAGO null mutations are either not tolerated or do not cause observable symptoms.…”

“…It is noteworthy that among the described NDD cases, frameshift mutations or large deletions that could result in unambiguous single-gene null mutations of hAGO1 or hAGO2 were rarely documented [22]. This suggests that the NDD-associated single amino acid mutations of hAGO1 or hAGO2 may be more malicious than either null allele, perhaps by antagonizing otherwise redundant paralogous AGO genes.…”