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Genetic approaches to human renal agenesis/hypoplasia and dysplasia
Simone Sanna-Cherchi1, Gianluca Caridi, Patricia L Weng
1Department of Medicine, Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
Insights
Congenital kidney and urinary tract abnormalities in children are complex genetic disorders. Identifying causative genes is challenging but crucial for diagnosis and treatment, requiring collaborative research efforts.
Area of Science:
- Pediatric Nephrology
- Human Genetics
- Developmental Biology
Background:
- Congenital abnormalities of the kidney and urinary tract (CAKUT) are common in children, leading to significant morbidity and mortality.
- These conditions exhibit high phenotypic variability and complex genetic underpinnings, complicating diagnosis and research.
- Current understanding largely stems from mouse models and rare syndromic forms of human CAKUT.
Purpose of the Study:
- To review the challenges and strategies in discovering genes responsible for CAKUT, specifically renal agenesis/hypoplasia and dysplasia.
- To highlight the need for molecular definition to improve clinical classification and diagnosis of these anomalies.
- To emphasize the potential of large, collaborative research groups in advancing the field.
Main Methods:
- Review of existing literature on genetic studies of CAKUT.
- Discussion of various genetic approaches including candidate gene studies, linkage analysis, and genome-wide variation analysis.
- Exploration of insights from developmental biology, focusing on ureteric bud-metanephric mesenchyme interactions.
Main Results:
- Genetic contributions to CAKUT are increasingly recognized, with implicated genes regulating key kidney development pathways.
- Despite various genetic strategies, identifying causative genes remains challenging due to disease heterogeneity and diagnostic difficulties.
- Successful gene discovery has been achieved through diverse approaches, though many cases remain unexplained.
Conclusions:
- Accurate molecular diagnosis is essential for improving the classification and understanding of CAKUT.
- Multicentric collaborative efforts are vital for pooling resources and expertise to overcome current research challenges.
- Further research is needed to unravel the complete genetic architecture of CAKUT and improve patient outcomes.
Abstract:
Congenital abnormalities of the kidney and urinary tract are frequently observed in children and represent a significant cause of morbidity and mortality. These conditions are phenotypically variable, often affecting several segments of the urinary tract simultaneously, making clinical classification and diagnosis difficult. Renal agenesis/hypoplasia and dysplasia account for a significant portion of these anomalies, and a genetic contribution to its cause is being increasingly recognized. Nevertheless, overlap between diseases and challenges in clinical diagnosis complicate studies attempting to discover new genes underlying this anomaly. Most of the insights in kidney development derive from studies in mouse models or from rare, syndromic forms of human developmental disorders of the kidney and urinary tract. The genes implicated have been shown to regulate the reciprocal induction between the ureteric bud and the metanephric mesenchyme. Strategies to find genes causing renal agenesis/hypoplasia and dysplasia vary depending on the characteristics of the study population available. The approaches range from candidate gene association or resequencing studies to traditional linkage studies, using outbred pedigrees or genetic isolates, to search for structural variation in the genome. Each of these strategies has advantages and pitfalls and some have led to significant discoveries in human disease. However, renal agenesis/hypoplasia and dysplasia still represents a challenge, both for the clinicians who attempt a precise diagnosis and for the geneticist who tries to unravel the genetic basis, and a better classification requires molecular definition to be retrospectively improved. The goal appears to be feasible with the large multicentric collaborative groups that share the same objectives and resources.
