ORCID Profile
0000-0002-4257-8623
Current Organisations
Harvard College
,
Howard Hughes Medical Institute
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Publisher: American Association for the Advancement of Science (AAAS)
Date: 2014
DOI: 10.1126/SCITRANSLMED.AAT1199
Abstract: Mutations in MYBPC3 disrupt myosin states of relaxation, and manipulating myosin therapeutically abates the effects of MYBPC3 mutations.
Publisher: Proceedings of the National Academy of Sciences
Date: 03-03-2021
Abstract: Genetics, notably pathogenic genetic variants in sarcomere protein genes, play a major role in development of hypertrophic cardiomyopathy (HCM). However, degree of contribution from epigenetic and environmental factors in clinical presentation of HCM is currently unclear. We investigated phenotypic differences between identical twins with pathogenic sarcomere protein gene variants and demonstrated their discordant HCM presentation despite having virtually identical genomes. Our study underscores the important contribution of epigenetics and environment in disease progression in genetically diagnosed HCM patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2021
DOI: 10.1161/CIRCGEN.121.003389
Abstract: Heterozygous TTN truncating variants cause 10% to 20% of idiopathic dilated cardiomyopathy (DCM). Although variants which disrupt canonical splice signals (ie, invariant dinucleotide of the splice donor site, invariant dinucleotide of the splice acceptor site) at exon-intron junctions are readily recognized as TTN truncating variants, the effects of other nearby sequence variations on splicing and their contribution to disease is uncertain. Rare variants of unknown significance located in the splice regions of highly expressed TTN exons from 203 DCM cases, 3329 normal subjects, and clinical variant databases were identified. The effects of these variants on splicing were assessed using an in vitro splice assay. Splice-altering variants of unknown significance were enriched in DCM cases over controls and present in 2% of DCM patients ( P =0.002). Application of this method to clinical variant databases demonstrated 20% of similar variants of unknown significance in TTN splice regions affect splicing. Noncanonical splice-altering variants were most frequently located at position +5 of the donor site ( P =4.4×10 7 ) and position -3 of the acceptor site ( P =0.002). SpliceAI, an emerging in silico prediction tool, had a high positive predictive value (86%–95%) but poor sensitivity (15%–50%) for the detection of splice-altering variants. Alternate exons spliced out of most TTN transcripts frequently lacked the consensus base at +5 donor and −3 acceptor positions. Noncanonical splice-altering variants in TTN explain 1-2% of DCM and offer a 10-20% increase in the diagnostic power of TTN sequencing in this disease. These data suggest rules that may improve efforts to detect splice-altering variants in other genes and may explain the low percent splicing observed for many alternate TTN exons.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-08-2022
Abstract: Pathogenic variants in genes that cause dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) convey high risks for the development of heart failure through unknown mechanisms. Using single-nucleus RNA sequencing, we characterized the transcriptome of 880,000 nuclei from 18 control and 61 failing, nonischemic human hearts with pathogenic variants in DCM and ACM genes or idiopathic disease. We performed genotype-stratified analyses of the ventricular cell lineages and transcriptional states. The resultant DCM and ACM ventricular cell atlas demonstrated distinct right and left ventricular responses, highlighting genotype-associated pathways, intercellular interactions, and differential gene expression at single-cell resolution. Together, these data illuminate both shared and distinct cellular and molecular architectures of human heart failure and suggest candidate therapeutic targets.
No related grants have been discovered for Barbara McDonough.