Novel Mutations in NPHP4 in a Consanguineous Family With Histological Findings of Focal Segmental Glomerulosclerosis

An approach to the diagnosis of hereditary kidney disease. Abbreviation: OMIM, Online Mendelian Inheritance in Man.

Family pedigree. The 10K single-nucleotide polymorphism (SNP) genotype calls identified a 5.8865-Mb homozygous region (5.0450 to 10.9315 Mb) on chromosome 1p in affected individuals. Sequencing the NPHP4 gene, located within this region, showed 2 novel homozygous missense sequence variants in exons 18 and 21 that segregated with disease in this family. At position c.2314, in exon 18, the reference sequence for the 2 alleles is C/C. The homozygous c.2314C→T variant leads to a p.R772C amino-acid substitution. At position c.3037, in exon 21, the reference sequence for the 2 alleles is G/G, the homozygous c.3037G→A variant leads to a p.E1013K amino-acid substitution. Black box, affected; white box, unaffected; hatched box, unknown.

Renal biopsy tissue from patient 11. Masson trichrome stain shows global (arrow) and segmental (arrowhead) glomerulosclerosis. There is moderate interstitial fibrosis and tubular atrophy. No cysts are noted, and tubular basement membranes are unremarkable. (Bar = 200 μm.)

Electron microscopy in patient 11 shows ultrastructural features of preserved podocyte foot processes (arrowheads) in some areas of the glomerular tuft and foot-process effacement (arrows) in other areas. This finding is suggestive of podocyte injury from a secondary cause, but also may occur in some hereditary forms of focal segmental glomerulosclerosis. (Bar = 2 μm.)