Detection of the NPHP4 c.2999_3005del (p.Asn1000SerfsTer4) variant in an Iranian family with nephronophthisis-4

Nephronophthisis type 4 (NPHP4) is a rare genetic kidney disorder progressing to end-stage renal disease (ESRD). In this study, we aimed to identify the genetic cause of NPHP4 in a pedigree with three affected individuals. Whole-exome sequencing was performed on the proband, and variants were filtered, analyzed, and evaluated using in silico tools. Co-segregation analysis was conducted using Sanger sequencing. Protein modeling for the wild-type and mutant forms was performed using AlphFold3. We identified a homozygous deletion (c.2999_3005delTGTGTGT/ p.Asn1000SerfsTer4) in exon 21 of NPHP4, which co-segregated with the disease in the pedigree, demonstrating an autosomal recessive inheritance. 3D protein modeling predicted significant structural changes due to the truncation. The results of this study reveal a deletion variant NPHP4 c.2999_3005del (p.Asn1000SerfsTer4) that causes NPHP4 disease. This study, as a second report of a variant, reaffirms this very variant's pathogenicity and illuminates a critical locus prone to disruption, enhancing our understanding of genotype-phenotype correlations in NPHP4. The concurrence of independent observations of the same variants in NPHP4 emphasizing C-terminal truncation strengthens evidence that disruption of this region is clinically relevant in NPHP4-related disease. These findings together can provide improved understanding of the genetic basis of the disease, therefore better guidance for genetic counseling and family planning strategies for additional affected families.