Genetic causes of congenital anomalies of the kidney and urinary tract

Introduction

Congenital anomalies of the kidneys and urinary tract (CAKUT) encompass many heterogenous anomalies of the kidney, ureter, bladder, and urethra ( Fig. 8.1 ). CAKUT is the leading cause of kidney disease and of renal failure in children. The prevalence of CAKUT is estimated by population studies to lie between 0.1% and 2%, with higher prevalence in preterm infants. CAKUT has a complex etiology with environmental and genetic risk factors identified. Ongoing research demonstrates that a growing portion of CAKUT is attributable to genetic disorders. These estimates vary widely by diagnostic method and the population studied. Large studies using genomic microarrays have found copy number variants (CNVs) in 5%–15% of cases of CAKUT. A significant portion of CAKUT is also caused by single-gene disorders diagnosed by genome-wide sequencing. Studies of large cohorts of individuals with CAKUT have demonstrated that 10%–20% have single-gene disorders. An unknown portion of CAKUT may be attributable to yet undescribed genetic diseases, as well as polygenic or epigenetic mechanisms.

Fig. 8.1, Congenital anomalies of the kidneys and urinary tract ( CAKUT ). CAKUT encompasses a broad array of anomalies affecting the kidney, ureter, bladder, or urethra. These anomalies vary widely in prevalence. PUV , posterior urethral valves; UPJO, ureteropelvic junction obstruction; UVJO, ureterovesical junction obstruction; VUR , vesicoreteral reflux.

Many of the implications of CAKUT to neonatal clinical management are unclear and are an active area of research. Intriguing questions and controversies exist in the diagnosis and management of CAKUT, specifically with regards to its genetic basis ( Box 8.1 ). To frame these questions, this chapter reviews evidence for the genetic basis of CAKUT, the genetic regulation of renal development, and the spectrum of clinical disease. This chapter concludes with a discussion of future directions of research through which these questions may be answered. This chapter is intended to be a resource for training and practicing neonatologists, nephrologists, pediatricians, and geneticists, as well as for researchers studying the renal system and its genetic architecture.

BOX 8.1

QUESTIONS AND CONTROVERSIES REGARDING THE GENETIC BASIS OF CONGENITAL ANOMALIES OF THE KIDNEYS AND URINARY TRACT

Recent advances in genomic sequencing and basic science have dramatically expanded our understanding of the genetic contribution to congenital anomalies of the kidneys and urinary tract (CAKUT). However, several areas remain unresolved.

1.
What is the missing heritability of CAKUT? Many genetic disorders cause CAKUT, yet these explain a fraction of cases. Compelling evidence indicates that a larger portion of CAKUT is heritable or genetically influenced. Novel methods are needed to explain this gap.
2.
What are the clinical benefits of genetic testing? CAKUT can be the heralding feature of syndromic disease that manifests later in life. Reduced cost and improved quality of care have been demonstrated for genetic testing in other congenital diseases. Clinical trials are needed to assess the full risks and benefits of genome-wide testing in CAKUT.
3.
How can genetic testing be more equitable? Genome-wide sequencing is now recommended as first-line testing for congenital anomalies such as CAKUT. However, testing is not universally available. Improved health-care approaches are needed to establish how to improve care in underserved communities. Inclusive population genomic studies are also needed to better understand the genetic basis of CAKUT in people of diverse backgrounds.
4.
What is the clinical significance of nonspecific anomalies? Many forms of CAKUT, such as unilateral renal agenesis, duplicated collecting system, or urinary tract dilation, are associated with highly variable impacts on health. Often they are benign, but they are also associated with progression to renal failure. Genetic testing may help stratify the significance of such anomalies. Studies involving screening, longitudinal follow-up, and genome-wide testing are needed, particularly in high-risk groups such as in infants admitted to the neonatal intensive care unit, to clarify the implications of anomalies.

Evidence for genetic basis

CAKUT, like all diseases, is caused by a combination of genetic and environmental factors. The precise balance of genetic and environmental contribution to CAKUT is unknown. Teratogen exposure, high or low levels of retinoic acid, and gestational diabetes each account for a small portion of CAKUT. ^, A growing body of evidence demonstrates that a portion of CAKUT is also caused by mendelian disorders, such as DiGeorge syndrome. Interestingly, factors traditionally described as environmental may themselves be genetically influenced. For example, preterm delivery, an “environmental” factor associated with arrest of nephrogenesis and renal hypoplasia, is itself a phenotype heavily influenced by genetic factors. Thus, even with a complete understanding of the etiology of CAKUT, quantifying its exact genetic contribution depends upon a somewhat arbitrary delineation. With this caveat in mind, a large body of literature has described the portion of CAKUT with genetic causes.

Twins

One of the foundational approaches to measure the heritability of traits is to assess concordance in twins. Twin studies assume that monozygotic and dizygotic twins share similar environments. Traits found to be more frequently concordant in monozygotic twins are therefore more likely to be genetically influenced. Twin studies and related family studies demonstrate high rates of concordance and familial clustering of multiple forms of CAKUT, therefore demonstrating a significant contribution of genetic factors to CAKUT etiology.

Mendelian inheritance

Further evidence of a genetic basis comes from studies of rare families with mendelian inheritance of CAKUT. ^, Segregation in these families usually demonstrates autosomal dominant inheritance of disease. Analysis of these families is often complicated by incomplete penetrance and variable expressivity of CAKUT phenotypes. Penetrance refers to whether an individual with a given genetic change manifests with a phenotype, whereas expressivity refers to different phenotypes found in individuals with the same genetic changes. In the context of CAKUT, individuals with the same genetic disorders may or may not manifest with renal anomalies (incomplete penetrance); and those individuals who do manifest renal anomalies may express different forms of CAKUT (variable expressivity). Despite this complexity, studies of affected families using classical genetics methods identified canonical CAKUT genes including HNF1B , EYA1, PAX2 . Familial cases represent a very small portion of CAKUT. The rarity of familial CAKUT has been hypothesized to occur due to reduced reproductive fitness in affected individuals, greater contribution to CAKUT on a population level from de novo variants, recessive disorders, polygenic and epigenetic mechanisms, as well as environmental factors. ^, ^, ^,

Single-gene disorders

The expanded use of genome-wide sequencing has demonstrated that approximately 10%–20% of individuals with CAKUT have single-gene disorders. ^, Several genes are frequently implicated in genome-wide studies. These include genes in the RET and WNT signaling pathways, as well as novel genes, such as GREB1L, which encodes a poorly characterized transcription factor associated with development of the brain, heart, and kidney. ^, ^, ^, Interestingly, although these genes are repeatedly found associated with CAKUT, they each account for a small fraction of genetic diagnoses. Indeed, rather than having just these few genes responsible for CAKUT, many genes are found in genome-wide studies of CAKUT. To date, approximately 50 CAKUT genes have been identified.

Copy number variants and aneuploidy

In addition to single and oligonucleotide variants, structural genomic disorders and aneuploidy cause a significant portion of CAKUT. A large study of adults with CAKUT found that 4% of individuals had known pathogenic CNVs and another 2% had novel, putatively pathogenic CNVs. Caruana et al. similarly found that as much as 10% of CAKUT in children could be attributable to CNVs. Fetal studies have identified aneuploidy in 13% and CNVs in 4%–15% of CAKUT cases. ^, As with genome-wide sequencing, using microarray-based studies, a small number of disorders are repeatedly found associated with CAKUT, but these each account for a small portion of disease. Disorders commonly found in individuals with CAKUT include CNVs at the loci 22q11 (associated with DiGeorge syndrome), 4p (Wolf-Hirschhorn syndrome), and 17q12 (renal cysts and diabetes [RCAD] syndrome). ^,

In addition to human genetics research, studies using basic animal models have been instrumental in determining the genetic basic of CAKUT. The novel CAKUT gene DSTYK was implicated in familial studies, then validated when its phenotype was recapitulated in knockout zebrafish and mouse models. Similar approaches discovered the novel CAKUT gene GREB1L and found that CRKL is the gene within the 22q11 locus likely responsible for renal anomalies in DiGeorge syndrome. ^, ^, In addition to confirming genetic findings, research in animals allows direct investigation of the mechanisms of disease pathogenesis. Much of what has been learned about the molecular regulation of renal development comes from such animal models.

Renal development

The renal system forms through a complex, developmental interplay between multiple cellular lineages, regulated by many transcriptional and signaling pathways. From approximately 6 to 36 weeks of gestation the metanephros develops into the kidney. The development of the metanephros itself depends upon the development and regression of the pronephros and mesonephros. The metanephros then develops through reciprocal signaling between the ureteric bud and the metanephric mesenchyme in a process known as branching morphogenesis. Through this process, the treelike structure of the renal pelvis, major and minor calyces, and smaller collecting ducts emerges. While this is taking place, the cells of the metanephric mesenchyme also divide and differentiate to form the nephron in a process known as nephrogenesis. Concurrent with branching morphogenesis and nephrogenesis, the early kidney also begins migrating cranially, and the tract of the ureters, bladder, and urethra continues to develop.

Manifestations of CAKUT often correspond to disruptions at specific time points in renal development. Disruptions that occur prior to 4–6 weeks are associated with renal agenesis; disruptions after 4–6 weeks are associated with renal hypoplasia; disruptions after 6–8 weeks are associated with renal ectopy, dysplasia, and obstructive uropathies.

Much of our understanding of the molecular regulation of renal development comes from study in model organisms such as the mouse. This work has demonstrated that RET signaling is necessary for nephrogenesis, particularly in regulating the interaction between the ureteric bud and metanephric mesenchyme. ^, The genes BMP4, HNF1B, EYA1, and RET participate in this pathway and are each associated with autosomal dominant forms of CAKUT. ^, ^, ^, Likewise, genes involved in WNT signaling regulate ureteric budding. Variants in the WNT pathway genes WNT4 and SIX2 are also found in autosomal dominant CAKUT.

Genes involved in CAKUT often have complex and overlapping roles within renal development. Thus, individuals with the same genetic disease may develop variable forms of CAKUT. For example, the murine orthologs of PAX2 and PAX8 have partially redundant roles in formation of the mouse kidney. Pathogenic variants in these genes cause renal agenesis, but with variable penetrance. ^, Similarly, individuals with variants in HNF1B may manifest with renal agenesis, hypoplasia, dysplasia, or cystic disease. Finally, genes associated with CAKUT are often involved in the development of other organs as well. Individuals presenting with CAKUT often have extrarenal manifestations, such as disease affecting the heart, brain, or liver.

Spectrum of congenital anomalies of the kidney and urinary tract

CAKUT can be grouped into the following categories: solitary or bilaterally absent kidney (SBK), ectopy or fusion (EF), renal hypoplasia or dysplasia (RHD), and urinary tract malformations or dilation (UTD). Several complex and rare forms of CAKUT, such as prune belly syndrome, do not fit easily into one category. These categories have clinical and research utility, as entities within each category often have similar pathogenic mechanisms and clinical implications. However, these categories have significant overlap. For example, the diagnosis of a solitary kidney may represent primary agenesis of one kidney, the resorption of a severely dysplastic kidney, or a pelvic kidney not detected on ultrasound. Likewise, a urinary tract malformation may result in isolated dilation of the renal pelvis or in dysplastic changes within the renal parenchyma. The categorization of CAKUT is particularly challenging when viewed through a genomic lens. CAKUT arising from genetic disorders has an unusually high degree of complexity in terms of phenotype and penetrance. Individuals with the same genetic disorder may have no clinically apparent disease, a minor renal anomaly, or a catastrophic congenital syndrome. Furthermore, individuals with similar presentations of CAKUT are often found to have many different genetic disorders. Thus, although these categorizations of CAKUT provide some usefulness in clinical practice and research, it is important to keep in mind their limitations.

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