Functional assessment of a novel splicing site variant in a Chinese X-linked Alport syndrome family.

BACKGROUND

Chronic kidney disease caused by X-linked Alport syndrome (XLAS) is relatively rare. However, due to the nonspecific pathologic and clinical manifestations of this disease, it is easily misdiagnosed. Genetic testing is crucial in identifying suspected cases. In addition, the results of genetic testing are an important indicator of patient prognosis. This study demonstrated a novel pathogenic splicing site variant in a Chinese family with XLAS.

METHODS

Targeted next generation sequencing (NGS) was performed to identify the gene variant in the family members, and the gene mutation site was confirmed by Sanger sequencing. We then further analyzed the consequences of this gene mutation on the translated protein of this variant using and approaches.

RESULTS

A novel splice region variant, c.1033-2(IVS 18) A>G, in intron 18 was identified in the affected family members. Sanger sequencing confirmed that this variant is segregated with disease. analysis, this variant led to frame-shift and premature termination on the translation of the nucleic acid, and this result was verified by RNA splicing analysis in a cell model. Unexpectedly, we still observed positive immunohistology staining of collagen IV α5 in the glomerular basement membrane (GBM) of the index patient, which implied that another potential transcription or translation mechanism skipping the mutated site might exist.

CONCLUSIONS

Our present finding expands the mutational spectrum for the gene associated with XLAS and highlights the genotype-phenotype correlations in this disease.