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Updated: Jun 19, 2025
11:09
Chromatin Isolation by RNA Purification ChIRP
Published on: March 25, 2012
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Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
Rebecca E Andersen1,2,3, Ibrahim F Alkuraya4,5, Abna Ajeesh4
1Division of Genetics and Genomics and Manton Center for Orphan Diseases, Boston Children's Hospital, Boston, MA, USA.
Human Genetics
|July 26, 2024
Summary
Chromosomal abnormalities disrupting long non-coding RNAs (lncRNAs) may cause Mendelian disorders. This study identified 66 cases where rearrangements directly impact lncRNAs, suggesting their role in developmental etiologies.
Area of Science:
- Genomics
- Molecular Biology
- Human Genetics
Background:
- The non-protein-coding genome, particularly long non-coding RNAs (lncRNAs), is increasingly recognized for its role in Mendelian disorders.
- Annotating pathogenic variants in lncRNAs is challenging due to their non-protein-coding nature.
Purpose of the Study:
- To investigate if chromosomal rearrangements disrupting lncRNAs are the genetic cause of phenotypes in individuals with apparently balanced chromosomal abnormalities (BCAs).
- To identify and characterize lncRNA disruptions in individuals with BCAs and potential developmental etiologies.
Main Methods:
- Analysis of 279 cases with BCAs, focusing on 191 cases with simple BCAs (two breakpoints).
- Identification of chromosomal rearrangements directly disrupting lncRNAs.
- Experimental validation of lncRNA function through knockdown studies.
Main Results:
- Identified 66 cases with chromosomal rearrangements directly disrupting lncRNAs.
- In 30 cases, only lncRNAs were disrupted, supporting their role in disease.
- Disruptions in MEF2C-AS1 and ENSG00000257522 were found in two unrelated cases each.
- Knockdown of TBX2-AS1 and MEF2C-AS1 reduced expression of neighboring transcription factors TBX2 and MEF2C, respectively.
Conclusions:
- Chromosomal rearrangements disrupting lncRNAs can be the genetic etiology for Mendelian disorders with developmental phenotypes.
- This genomic approach is powerful for annotating disease-causing lncRNAs.
- Seven individuals with likely developmental etiologies due to lncRNA disruptions are presented with clinical and genetic analyses.
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