Clinical Report: Identification of a Unique Non-Canonical Splice Site Variant in COL4A5
Overview
This case study reports a novel non-canonical splice site variant in the COL4A5 gene associated with Alport syndrome in a pediatric patient. Functional validation confirmed the pathogenicity of the variant.
Background
Alport syndrome is a genetically diverse disorder characterized by progressive renal impairment and is often complicated by sensorineural hearing loss. Accurate diagnosis is crucial for timely intervention, yet non-canonical splice site variants can complicate genetic testing and interpretation.
Data Highlights
The proband was diagnosed with a hemizygous COL4A5 variant (NM_033380.3: c.3374-3T > G) confirmed through whole-exome sequencing. The minigene splicing assay demonstrated that this variant leads to exon 38 skipping, establishing its pathogenicity.
Key Findings
The proband presented with microscopic hematuria and was diagnosed with Alport syndrome.
A novel non-canonical splice site variant (c.3374-3T > G) in the COL4A5 gene was identified.
Functional validation through a minigene splicing assay confirmed aberrant mRNA splicing.
This variant expands the mutational spectrum of Alport syndrome.
Integration of whole-exome sequencing and functional assays is critical for accurate diagnosis.
Clinical Implications
Advanced genetic testing, including functional assays, may be considered for patients with suspected Alport syndrome, particularly when faced with non-canonical splice site variants.
Conclusion
This study highlights the role of functional validation in the diagnosis of Alport syndrome for variants that are not easily interpreted through standard genetic testing.
