2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Resolution of Variants of Uncertain Significance by RNA Sequencing

Pdf Summary

This study focuses on the use of RNA sequencing (RNA-Seq) to resolve variants of uncertain significance (VUSs) in individuals with rare diseases. The researchers used RNA-Seq to analyze tissue samples from affected individuals and control samples from the Genotype-Tissue Expression project. They found that RNA-Seq was able to support the interpretation of intronic variants in the TRAPPC12 gene and the DYNC2H1 gene. These variants were initially classified as VUSs but were reclassified as likely pathogenic based on the RNA-Seq data.<br /><br />In the case of TRAPPC12, a female with epilepsy and intellectual disability was found to have two heterozygous intronic variants. These variants were reclassified as likely pathogenic based on the RNA-Seq data. In the case of DYNC2H1, a male with post-axial polydactyly and chest abnormalities was found to have two variants, one of which was intronic and initially classified as a VUS. However, RNA-Seq data supported the reclassification of the intronic variant as likely pathogenic.<br /><br />The study also identified a variant in the ACADM gene associated with medium-chain acyl-CoA dehydrogenase deficiency. Clinical sequencing had initially identified one likely pathogenic variant, but RNA-Seq helped discover a second variant that explained the patient's phenotype. In another case, RNA-Seq helped identify a second variant in the CEP120 gene, which was the most interesting candidate for a pair of siblings with abnormal brain findings.<br /><br />Overall, this study demonstrates the utility of RNA-Seq in resolving VUSs in rare genetic diseases. The researchers suggest that RNA-Seq could be considered as a follow-up clinical test in cases where additional data is needed after inconclusive genetic testing.

Asset Subtitle

Presenting Author - Aren E. Marshall, PhD; Co-Author - Giulia F. Del Gobbo, PhD; Co-Author - Yijing Liang, MHSc; Co-Author - Madeline Couse, MSc; Co-Author - Kym M. Boycott, MD, PhD, FRCPC, FCCMG; Co-Author - Kristin D. Kernohan, PhD, FCCMG;

Meta Tag

Bioinformatics

Clinical Applications of Molecular Cytogenetics

Companion Diagnostics

Exome sequencing

Genetic Testing

Genome sequencing

Genomic Methodologies

Genotype-Phenotype Correlations

Methodology

Molecular Cytogenetics

NextGen Sequencing

Pathogenesis

Polymorphism

Sequencing

Variant Detection

Co-Author Giulia F. Del Gobbo, PhD

Co-Author Yijing Liang, MHSc

Co-Author Madeline Couse, MSc

Co-Author Kym M. Boycott, MD, PhD, FRCPC, FCCMG

Co-Author Kristin D. Kernohan, PhD, FCCMG

Presenting Author Aren E. Marshall, PhD

Keywords

RNA sequencing

RNA-Seq

variants of uncertain significance

VUSs

rare diseases

TRAPPC12 gene

DYNC2H1 gene

likely pathogenic

ACADM gene

medium-chain acyl-CoA dehydrogenase deficiency