Genetic etiology of inherited kidney diseases in egyptian patients: next generation sequencing identifies six novel variants

TL;DR

This study identifies six new genetic mutations linked to inherited kidney diseases in Egyptian patients, highlighting the importance of genetic testing in consanguineous populations.

Contribution

The study reports six novel genetic variants associated with inherited kidney diseases in a consanguineous Egyptian population.

Findings

Seventeen distinct variants were identified in 12 genes, including six novel mutations.

Alport Syndrome was the most frequent disorder, with COL4A3 and COL4A5 mutations predominating.

FREM1 variants were linked to syndromic kidney disease, and consanguinity supported autosomal recessive inheritance patterns.

Abstract

Inherited kidney diseases (IKDs) are a significant cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD), especially in children. While next-generation sequencing (NGS) has enhanced IKD diagnosis, data from consanguineous populations, where autosomal recessive inheritance is more common, remain limited.

This study aimed to identify genetic variants associated with IKDs, primarily from consanguineous Egyptian families, using targeted next-generation sequencing (NGS). It further assessed genotype–phenotype correlations and explored clinical implications for early diagnosis, familial screening, and disease management.

Twenty-six Egyptian patients clinically suspicion with IKDs were enrolled. Targeted NGS was conducted using a gene panel associated with IKDs. Variants were classified per American College of Medical Genetics and Genomics (ACMG) guidelines. Segregation analysis was performed when possible. In silico tools, including VarSome, I-Mutant 2.0, and GeneMANIA, were used to predict variant pathogenicity, protein impact, and gene–gene interactions.

Seventeen distinct variants were detected in 12 genes, including six novel mutations. Alport Syndrome was the most frequent disorder, with COL4A3 and COL4A5 mutations predominating. A novel COL4A3 variant (c.3926C > A) was identified, reinforcing the role of collagen gene mutations. FREM1 variants, including two novel ones, were linked to syndromic IKDs. AGT and ACE variants were associated with renal tubular dysgenesis, while PKD1 and PKHD1 mutations indicated both dominant and recessive polycystic kidney disease. High consanguinity supported autosomal recessive patterns.

This study expands the mutational spectrum of IKDs in an underrepresented population and highlights the utility of targeted NGS in guiding early diagnosis, genetic counseling, and personalized management in high-risk, consanguineous populations.

The online version contains supplementary material available at 10.1186/s40348-025-00203-2.

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