Molecular biology reports · 2026
Clinical and Molecular characteristics of kidney and urinary tract congenital anomalies in a cohort of Egyptian patients using whole-exome sequencing.
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Ammar Tamer H A, Ahmed Heba Mostafa, Mohammed Eman E A, El-Hariri Hazem Mohamed, Abdelaleem Alice, Thomas Manal M
Аннотация
BACKGROUND: Congenital abnormalities of the kidney and urinary tract (CAKUT) are the leading cause of pediatric end-stage renal disease, affecting 3-6 per 1,000 live births. Genetic mutations underlie approximately 30% of cases, necessitating next-generation sequencing for precise diagnosis.
AIMS: This study aims to identify the genetic etiology of CAKUT within a cohort of ten Egyptian patients (mean age 6.38 ± 3.52 years) presenting with diverse phenotypes, including renal agenesis, hypoplasia, and ureteric anomalies.
MATERIALS AND METHODS: Patients underwent comprehensive clinical evaluation, including pedigree construction, ultrasonography, and scintigraphy. Solo whole-exome sequencing (WES) was performed to identify underlying variants. Candidate variants were correlated with phenotypes and validated via Sanger sequencing, with pathogenicity assessed according to ACMG guidelines.
RESULTS: WES identified ten disease-associated variants across eight genes. Key findings include a novel heterozygous likely pathogenic frameshift variant (c.651delA: p.S217fs) in RIT1, causing Noonan syndrome type 8 (NS-8) in a patient with unilateral renal atrophy. Additional variants included a heterozygous COL4A3 VUS (Alport syndrome), a REN VUS (autosomal dominant tubulointerstitial kidney disease), and biallelic CLCNKB variants (Bartter syndrome type 3). Genetic signatures were also identified in PKD1, PKHD1, FRAS1, and WNT9B.
CONCLUSION: WES is a high-yield diagnostic tool for CAKUT. This study provides the first report of a RIT1 mutation in Egypt and the first confirmed association of RIT1 with renal anomalies in NS-8. Expanding genomic screening and incorporating copy number variant (CNV) analysis are essential to fully define the mutation spectrum and improve clinical management for Egyptian CAKUT patients.
AIMS: This study aims to identify the genetic etiology of CAKUT within a cohort of ten Egyptian patients (mean age 6.38 ± 3.52 years) presenting with diverse phenotypes, including renal agenesis, hypoplasia, and ureteric anomalies.
MATERIALS AND METHODS: Patients underwent comprehensive clinical evaluation, including pedigree construction, ultrasonography, and scintigraphy. Solo whole-exome sequencing (WES) was performed to identify underlying variants. Candidate variants were correlated with phenotypes and validated via Sanger sequencing, with pathogenicity assessed according to ACMG guidelines.
RESULTS: WES identified ten disease-associated variants across eight genes. Key findings include a novel heterozygous likely pathogenic frameshift variant (c.651delA: p.S217fs) in RIT1, causing Noonan syndrome type 8 (NS-8) in a patient with unilateral renal atrophy. Additional variants included a heterozygous COL4A3 VUS (Alport syndrome), a REN VUS (autosomal dominant tubulointerstitial kidney disease), and biallelic CLCNKB variants (Bartter syndrome type 3). Genetic signatures were also identified in PKD1, PKHD1, FRAS1, and WNT9B.
CONCLUSION: WES is a high-yield diagnostic tool for CAKUT. This study provides the first report of a RIT1 mutation in Egypt and the first confirmed association of RIT1 with renal anomalies in NS-8. Expanding genomic screening and incorporating copy number variant (CNV) analysis are essential to fully define the mutation spectrum and improve clinical management for Egyptian CAKUT patients.