Alport Syndrome-Associated Pathogenic COL4A4 Variant in Sisters With Chronic Kidney Disease: Clinical Findings and...

Pathogenic variants in the COL4A4 gene lead to Alport syndrome, a hereditary kidney disorder characterized by deficiencies in the glomerular basement membrane (GBM), progressive renal failure, and associated visual and auditory dysfunctions.

This study is aimed at detecting genetic variants and conducting an integrative network analysis to elucidate their involvement in Alport syndrome and chronic kidney disease (CKD).

The enrolled patients were biological sisters. Clinical and pathological data were collected using laboratory tests. Genetic testing was performed to identify the variants via whole-exome sequencing (WES). The pathogenicity of the detected variant was confirmed using different computational approaches. The detected variants were classified according to the ACMG criteria. The interaction networks of CKD, Alport syndrome, and COL4A4 were examined using STRING v11.5, whereas pathways were analyzed by KEGG and STRING pathways analysis.

Patients were diagnosed with CKD of Stage 5. The ultrasound results were not clear due to kidney fibrosis. WES revealed an 18-base pair deletion in the COL4A4 gene (chr2: g.227958874_227958891del). The detected variant was classified as pathogenic by ACMG criteria. Online Mendelian Inheritance in Man (OMIM) reveals that the variant in COL4A4 is due to autosomal recessive Alport syndrome 2. Sensorineural hearing loss was observed in two family members of the patients. These results show the existence of Alport syndrome in their family. The disease-protein interaction by STRING reveals that the COL4A4 protein is strongly associated with both CKD and Alport syndrome diseases. KEGG analysis indicates a consistent association of PI3K-Akt and AGE-RAGE pathways among both diseases.

Dysfunction of COL4A4 leads to disruptions in GBM structure and signaling, which hasten CKD in Alport syndrome. Genetic testing is essential for identifying the exact cause of the disease, which aids in early diagnosis and control to spread within families.