Clinical Report: Characterization and pathogenic assessment of a new intronic variant in the COL4A5 gene within a Chinese family
Overview
This study identifies a novel intronic variant in the COL4A5 gene associated with X-linked Alport syndrome in a Chinese family. Functional assays confirm that this variant leads to abnormal splicing, contributing to the disease phenotype.
Background
X-linked Alport syndrome (XLAS) is a hereditary disorder characterized by renal impairment, hearing loss, and ocular anomalies due to mutations in the COL4A5 gene. Accurate genetic diagnosis is crucial for understanding disease severity and guiding management. Despite the importance of splicing variants, their functional implications are often overlooked in clinical practice.
Data Highlights
Variant
Location
Effect
c.1587+4A>G
Intron 23
Abnormal splicing, exon 23 skipping
Key Findings
A novel splice variant (c.1587+4A>G) in COL4A5 was identified in a Chinese family.
The variant co-segregated with the disease phenotype in affected relatives.
Functional assays demonstrated that the variant causes exon 23 skipping and a frameshift mutation.
The proband exhibited microhematuria and had relatives with a history of renal disease.
Immunofluorescence analysis showed a lack of α5 chain expression in the proband's epidermal basement membrane.
Clinical Implications
This study highlights the importance of considering intronic variants in genetic testing for Alport syndrome. Clinicians should be aware that such variants can lead to significant splicing defects, impacting patient management and genetic counseling.
Conclusion
The identification of the c.1587+4A>G variant expands the known mutational spectrum of COL4A5 in XLAS and emphasizes the need for transcript analysis in cases of suspected splicing defects.
