Wednesday, October 2, 2024 at 12:00 PM
This grand round has already taken place.
October 2nd, 2024 1.00 AMA PRA Category 1 Credit Hours
Description
Abstract to our recently published manuscript (Hum Genet. 2024 Jul;143(7):921-938. doi: 10.1007/s00439-024-02693-y.Epub 2024 Jul 2)
In recent years, there has been increased focus on exploring the role the non-protein-coding genome plays in Mendelian disorders. One class of particular interest is long non-coding RNAs (lncRNAs), which has recently been implicated in the regulation of diverse molecular processes. However, because lncRNAs do not encode protein, there is uncertainty regarding what constitutes a pathogenic lncRNA variant, and thus annotating such elements is challenging. The Developmental Genome Anatomy Project (DGAP) and similar projects recruit individuals with apparently balanced chromosomal abnormalities (BCAs) that disrupt or dysregulate genes in order to annotate the human genome. We hypothesized that rearrangements disrupting lncRNAs could be the underlying genetic etiology for the phenotypes of a subset of these individuals. Thus, we assessed 279 cases with BCAs and selected 191 cases with simple BCAs (breakpoints at only two genomic locations) for further analysis of lncRNA disruptions. From these, we identified 66 cases in which the chromosomal rearrangements directly disrupt lncRNAs. In 30 cases, no genes of any other class aside from lncRNAs are directly disrupted, consistent with the hypothesis that lncRNA disruptions could underly the phenotypes of these individuals. Strikingly, the lncRNAs MEF2C-AS1 and ENSG00000257522 are each disrupted in two unrelated cases. Furthermore, we experimentally tested the lncRNAs TBX2-AS1 and MEF2C-AS1 and found that knockdown of these lncRNAs resulted in decreased expression of the neighboring transcription factors TBX2 and MEF2C, respectively. To showcase the power of this genomic approach for annotating lncRNAs, here we focus on clinical reports and genetic analysis of seven individuals with likely developmental etiologies due to lncRNA disruptions.
Dates and Times
Start: 10/2/2024 12:00 PM
End: 10/2/2024 1:00 PM
Objectives
1. The noncoding genome represents a large percentage of our genome yet we have focused largely on the 2% that is protein coding.
2. lncRNAs are largely characterized by a smaller size and specific orientation with regard to the protein coding gene it regulates.
3. lncRNAs may be the etiologies of rare disease patients and are generally not present on gene panels.
Speakers
Accreditation
The School of Medicine, State University of New York at Stony Brook, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The School of Medicine, State University of New York at Stony Brook designates this live activity for a maximum of 1.00 AMA PRA Category 1 Credits ™. Physicians should only claim the credit commensurate with the extent of their participation in the activity.
Need help with this Grand Round Session?
Please contact the Grand Round coordinator listed below:
Amy Loughlin
Department: Pathology
Phone: (631) 444-3000
Email: Amy.loughlin@stonybrookmedicine.edu