Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders

• DOI: 10.1007/s00439-024-02693-y
• Publication Date: 2024-07-26T21:05:15Z
• Authors: Rebecca E. Andersen; Ibrahim F. Alkuraya; Abna Ajeesh; Tyler Sakamoto; Elijah L. Mena; Sami S. Amr; Hila Romi; Margaret A. Kenna; Caroline D. Robson; Ellen S. Wilch; Katarena Nalbandian; Raul Piña-Aguilar; Christopher A. Walsh; Cynthia C. Morton
• Keywords: Human genetics

Abstract In recent years, there has been increased focus on exploring the role non-protein-coding genome plays in Mendelian disorders. One class of particular interest is long non-coding RNAs (lncRNAs), which recently implicated regulation diverse molecular processes. However, because lncRNAs do not encode protein, uncertainty regarding what constitutes a pathogenic lncRNA variant, and thus annotating such elements challenging. The Developmental Genome Anatomy Project (DGAP) similar projects recruit individuals with apparently balanced chromosomal abnormalities (BCAs) that disrupt or dysregulate genes order to annotate human genome. We hypothesized rearrangements disrupting could be underlying genetic etiology for phenotypes subset these individuals. Thus, we assessed 279 cases BCAs selected 191 simple (breakpoints at only two genomic locations) further analysis disruptions. From these, identified 66 directly lncRNAs. 30 cases, no any other aside from are disrupted, consistent hypothesis disruptions underly Strikingly, MEF2C-AS1 ENSG00000257522 each disrupted unrelated cases. Furthermore, experimentally tested TBX2-AS1 found knockdown resulted decreased expression neighboring transcription factors TBX2 MEF2C , respectively. To showcase power this approach lncRNAs, here clinical reports seven likely developmental etiologies due