The genetics and pathogenesis of CAKUT

Area of Science:

• Genetics
• Developmental Biology
• Nephrology

Background:

• Congenital anomalies of the kidney and urinary tract (CAKUT) represent a spectrum of malformations impacting kidney and urinary tract development.
• CAKUT are a significant cause of chronic kidney disease in children and young adults, accounting for nearly 50% of cases.
• The etiology of CAKUT is multifactorial, involving genetic mutations, copy number variants, and environmental/epigenetic factors.

Purpose of the Study:

• To highlight the genetic basis of CAKUT and the challenges in identifying novel causative genes.
• To emphasize the importance of discovering new CAKUT genes for improved clinical outcomes.
• To underscore the potential for personalized therapeutic strategies in CAKUT management.

Main Methods:

• Review of existing literature on genetic causes of CAKUT.
• Analysis of mutation data and copy number variants associated with CAKUT.
• Discussion of challenges in genotype-phenotype correlation and gene discovery.

Main Results:

• Monogenic mutations in approximately 54 genes are identified causes of CAKUT, contributing to 12-20% of cases.
• Pathogenic copy number variants are detected in 4-11% of CAKUT patients.
• Variable expressivity, incomplete penetrance, and genotype-phenotype correlation complicate novel gene discovery.

Conclusions:

• Identifying novel CAKUT-associated genes is crucial for advancing molecular genetic diagnosis.
• Improved understanding of CAKUT genetics can lead to better prognostic assessments.
• Discovery of new genetic factors may enable personalized and multidisciplinary clinical management strategies for CAKUT.