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2023 ACMG Annual Clinical Genetics Meeting Digital ...
Resolution of Variants of Uncertain Significance b ...
Resolution of Variants of Uncertain Significance by RNA Sequencing
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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
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