2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Missing heritability for supravalvar aortic stenosis identified in long range enhancer for elastin

Pdf Summary

This study investigates the genetic basis of supravalvar aortic stenosis (SVAS) in individuals without variations in the elastin gene (ELN) that are known to cause the condition. SVAS is often caused by variants in ELN, but some individuals with SVAS do not have identifiable variations in ELN. The researchers identified four individuals with SVAS who have atypical deletions of chromosome 7q11.2 that spare ELN. The deletions range in size from 255 Kb to 1.5 Mb and end 30-90 Kb upstream of ELN. Further analysis suggests that these deletions affect ELN expression, as RNA sequencing shows that ELN is predominantly expressed from a single allele in patients with SVAS and atypical deletions. Long read DNA sequencing confirms that the allele with decreased ELN expression is inherited in cis with the deletion. The researchers also identified potential regulatory elements upstream of ELN that may affect its transcription. These regulatory elements were identified using data from ENCODE and GeneHancer databases and showed high H3K27 acetylation and high DNase sensitivity, indicating open chromatin and potential regulatory regions. Overall, this study suggests that deletions far upstream of ELN may contribute to the development of SVAS by affecting its expression. Further studies are needed to fully understand the role of these regulatory elements in ELN expression and SVAS development.

Asset Subtitle

Co-Author - Sara Procknow, MD, PhD; Co-Author - Kit Man Tsang, PhD; Co-Author - Teresa R. Luperchio, PhD; Co-Author - Charles Billington, Jr, MD, PhD, FACMG; Co-Author - Kara Small, MSGC; Co-Author - Angela E. Scheuerle, MD, FAAP, FACMG; Co-Author - David H. Tegay, DO; Co-Author - Patricia Fernandez-Ferri, PhD; Co-Author - Jeanne M. Meck, PhD; Presenting Author - Beth Kozel, MD, PhD, FACMG;

Meta Tag

array CGH

Bioinformatics

Cardiac/circulatory disorders

Genetic Testing

Genome sequencing

Genotype-Phenotype Correlations

Co-Author Sara Procknow, MD, PhD

Co-Author Kit Man Tsang, PhD

Co-Author Teresa R. Luperchio, PhD

Co-Author Charles Billington, Jr, MD, PhD, FACMG

Co-Author Kara Small, MSGC

Co-Author Angela E. Scheuerle, MD, FAAP, FACMG

Co-Author David H. Tegay, DO

Co-Author Patricia Fernandez-Ferri, PhD

Co-Author Jeanne M. Meck, PhD

Presenting Author Beth Kozel, MD, PhD, FACMG

Keywords

supravalvar aortic stenosis

genetic basis

ELN gene

chromosome 7q11.2 deletions

ELN expression

RNA sequencing

long read DNA sequencing

regulatory elements

ENCODE database

GeneHancer database