Unusual Glomerular Abnormalities in a Patient With Combined COL4A5-NPHS1 Variants.

The collagen4α5 (gene COL4A5) isoform is an essential part of the glomerular basement membrane (GBM) lamina densa. Pathogenic variants in COL4A5 are associated with X-linked Alport syndrome. Nephrin (gene NPHS1) is a major component of the podocyte slit diaphragm. Pathogenic NPHS1 variants are autosomal recessive and manifest as childhood proteinuria. A 5-year-old girl with a family history of Alport syndrome presented with recurrent hematuria and proteinuria, normal renal function, and no hearing or ocular abnormalities. Genetic analysis and whole exome sequencing identified pathogenic heterozygous COL4A5 c.1633G>A (p.G545S) and NPHS1 c.2417C>A (p.A806D) variants in the patient and her father and sister. The kidney biopsy revealed focal segmental mesangial expansion and small foci of chronic tubulointerstitial change. In addition to the characteristic Alport changes, electron microscopy revealed highly unusual malformations of the capillaries and mesangium with multiple interrupted GBMs, absence of normal capillary endothelium, aberrant collagen formation foci, and abnormal mesangial structure. A literature analysis identified 3 additional patients aged 2.5-6 years with combined COL4A5-NPHS1 variants and similar clinical symptoms. We hypothesize that Alport-associated alterations in the positioning of extracellular matrix proteins in the GBM and changes in nephrin-associated signaling combine to affect developmental cues, resulting in this striking phenotype.