Rare Germline Disorders Implicate Long Non-coding RNAs Disrupted by Chromosomal Structural Rearrangements

Overview

Journal medRxiv

Date 2024 Jul 1

PMID 38946951

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 Pina-Aguilar

Christopher A Walsh

Cynthia C Morton

Affiliations

Soon will be listed here.

Abstract

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. Strikingly, the lncRNAs and are each disrupted in two unrelated cases. Furthermore, 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. To showcase the power of this genomic approach for annotating lncRNAs, here we focus on clinical reports and genetic analysis of two individuals with BCAs and additionally highlight six individuals with likely developmental etiologies due to lncRNA disruptions.

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