Alternative Isoforms May Refine Variant Interpretation

Long-read transcript sequencing uncovered protein-altering variants missed by reference transcript analyses and identified functional effects for a lung-specific DPP9 isoform.

By
Andrea Surnit
June 29, 2026
4 min

MDSpire News

Overview

This study reveals that many disease-associated variants are missed when relying solely on reference transcripts. The researchers demonstrated functional effects of a lung-specific DPP9 isoform linked to severe COVID-19 and pulmonary fibrosis.

Background

Understanding the impact of genetic variants on protein function is crucial for disease diagnosis and treatment. Traditional analyses often overlook tissue-specific isoforms, which can harbor significant genetic variation. This study aims to refine variant interpretation by integrating long-read RNA sequencing data with existing genetic databases.

Data Highlights

The study identified approximately 40,000 Genome-Wide Association Studies variants mapping to annotated alternative exons compared to 24,000 mapping to reference exons. About 80% of alternative transcripts containing disease-associated variants were not represented in current reference genome annotations.

Key Findings

Alternative isoform-specific exons had a greater burden of genetic variation than reference exons.
Approximately 80% of alternative transcripts with disease-associated variants were not included in current reference genome annotations.
Computational analyses prioritized multiple missense variants predicted to alter protein structure or stability in alternative isoforms.
The common DPP9 variant associated with severe COVID-19 was found within an unannotated alternative first exon.
Biochemical experiments demonstrated altered enzymatic properties due to the leucine-to-proline substitution in the DPP9 isoform.

Clinical Implications

Incorporating alternative transcript isoforms into genetic variant analysis may enhance the identification of protein-coding consequences.

Conclusion

The findings indicate that evaluating genetic variants within tissue-specific alternative transcript isoforms may uncover protein-coding consequences that are often missed by traditional analyses.