Rare germline disorders implicate long non-coding RNAs disrupted by chromosomal structural rearrangements

Area of Science:

• Genomics
• Non-coding RNA 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 whether chromosomal rearrangements disrupting lncRNAs are the genetic etiology for phenotypes in individuals with apparently balanced chromosomal abnormalities (BCAs).
• To enhance the annotation of lncRNAs using genomic disruption data.

Main Methods:

• Analysis of 279 cases with BCAs, focusing on 191 cases with simple BCAs (two breakpoints).
• Identification of chromosomal rearrangements directly disrupting lncRNAs.
• Clinical reporting and genetic analysis of affected individuals.

Main Results:

• Sixty-six cases with chromosomal rearrangements directly disrupting lncRNAs were identified.
• Two specific lncRNAs, MEF2C-AS1 and ENSG00000257522, were each disrupted in two unrelated cases.
• Thirty cases showed disruptions solely in lncRNAs, suggesting their potential role in observed phenotypes.

Conclusions:

• Chromosomal rearrangements disrupting lncRNAs can be a significant cause of Mendelian and developmental disorders.
• This genomic approach is powerful for annotating lncRNA function and identifying disease-causing variants.