Genetics of Autosomal Recessive Polycystic Kidney Disease and Its Differential Diagnoses

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) is a hepatorenal fibrocystic disorder that is characterized by enlarged kidneys with progressive loss of renal function and biliary duct dilatation and congenital hepatic fibrosis that leads to portal hypertension in some patients. Mutations in the PKHD1 gene are the primary cause of ARPKD; however, the disease is genetically not as homogeneous as long thought and mutations in several other cystogenes can phenocopy ARPKD. The family history usually is negative, both for recessive, but also often for dominant disease genes due to de novo arisen mutations or recessive inheritance of variants in genes that usually follow dominant patterns such as the main ADPKD genes PKD1 and PKD2. Considerable progress has been made in the understanding of polycystic kidney disease (PKD). A reduced dosage of disease proteins leads to the disruption of signaling pathways underlying key mechanisms involved in cellular homeostasis, which may help to explain the accelerated and severe clinical progression of disease course in some PKD patients. A comprehensive knowledge of disease-causing genes is essential for counseling and to avoid genetic misdiagnosis, which is particularly important in the prenatal setting (e.g., preimplantation genetic diagnosis/PGD). For ARPKD, there is a strong demand for early and reliable prenatal diagnosis, which is only feasible by molecular genetic analysis. A clear genetic diagnosis is helpful for many families and improves the clinical management of patients. Unnecessary and invasive measures can be avoided and renal and extrarenal comorbidities early be detected in the clinical course. The increasing number of genes that have to be considered benefit from the advances of next-generation sequencing (NGS) which allows simultaneous analysis of a large group of genes in a single test at relatively low cost and has become the mainstay for genetic diagnosis. The broad phenotypic and genetic heterogeneity of cystic and polycystic kidney diseases make NGS a particularly powerful approach for these indications. Interpretation of genetic data becomes the challenge and requires deep clinical understanding.

Keywords: ADPKD; DZIP1L; HNF1β/TCF2; PKD1/PKD2; PKHD1; autosomal recessive polycystic kidney disease (ARPKD); ciliopathies; nephronophthisis (NPHP).

Figure 1

Autosomal recessive polycystic kidney disease (ARPKD). (A) Baby with distended abdomen due to voluminous kidneys that lead to respiratory problems. (B) Abdominal situs of a perinatally demised ARPKD patient with symmetrically enlarged kidneys that maintain their reniform configuration. (C) Cross section of an ARPKD kidney with cortical extension of fusiform and cylindrical spaces arranged radially throughout the renal parenchyma from medulla to cortex. (D,E) Microscopically, fusiform dilations of renal collecting ducts and distal tubuli lined by columnar or cuboidal epithelium. These dilated collecting ducts run perpendicular to the renal capsule. (F) Obligatory hepatobiliary changes in ARPKD known as ductal plate malformation characterized by dysgenesis of the hepatic portal triad with hyperplastic biliary ducts and congenital hepatic fibrosis. (G–I) Renal ultrasound of young children with ARPKD demonstrating enlarged echogenic kidneys with fusiform dilations of collecting ducts and distal tubules arranged radially throughout the renal parenchyma from medulla to cortex.

Figure 2

Shown are the structures of polycystin-1, polycystin-2, and fibrocystin/polyductin, the main proteins for ADPKD and ARPKD that form a protein network in polycystic kidney disease and interact with each other. Polycystin-1 and polycystin-2 are ciliary multipass transmembrane proteins, while fibrocystin/polyductin represents a type 1-membrane protein, each with an intracellular C-terminal end. The proteins’ functions are still not fully understood, but roles, e.g., as mechanoreceptor involved in cell cycle regulation, planar cell polarity, and cell–cell and cell–matrix interactions have been discussed. Polycystin-2 (also known as TRPP2) is a member of the TRP (transient receptor potential) channel family and a non-selective cation channel important for Ca²⁺-homeostasis, etc. Both for polycystin-1 and for fibrocystin/polyductin, processed isoforms in the cytoplasma and the nucleus have been described that underlie regulated intramembrane proteolysis and may serve as transcription factors [from Bergmann (33); 9:151–180].

Figure 3

(A,B) Typical sonographic picture of ADPKD in a 10-month-old girl (A) and an 11-year-old boy (B). (C) ADPKD resembling ARPKD in a 3-year-old boy with enlarged echogenic kidneys and small sized cysts. (D) Three-week-old girl with previous oligohydramnion, arterial hypertension, and small cysts in massively enlarged kidneys with a calculated total kidney volume of about 100 ml (normal age-related value <40 ml). Her mother’s phenotype resembled ADPKD, but the family was shown to carry an HNF1β germline mutation [from Bergmann (5)].

Figure 4

Autosomal recessive inheritance. PKHD1 mutations and most ciliopathies are inherited in a recessive mode, however, importantly also mutations in dominant disease genes such as PKD1 and PKD2 can follow autosomal recessive traits. The family history usually is negative. Both, father and mother, are healthy and typically carry an “unfavorable” recessive disease allele in heterozygous state which is not sufficient to manifest the disease, however. By definition, both disease alleles need to be mutated in affected individuals with autosomal recessive disease. The recurrence risk for parents of a child with ARPKD is 25%. In contrast, the risk of patients to give birth to children with the same disease is insignificant and less than 1% in case the patient’s partner does not originate from the same family (consanguineous marriage), is not equally affected and the disease is not present in the partner’s pedigree.

Figure 5

Autosomal dominant inheritance due to a de novo mutation in PKD1, PKD2, or HNF1β, for example, which may mimic ARPKD. As in autosomal recessive inheritance, the family history is unremarkable and both parents are healthy. For the rest of the family as well as for parents and patients, it is of major importance to know if they are afflicted by a recessive or a dominant disease due to a de novo arisen mutation. The latter means that there is practically no recurrence risk for future children neither for the parents nor for other family members. In contrast, the affected patients themselves bear a 50% risk to pass the (dominant) mutation to their own future children (in contrast to ARPKD in which there is practically no risk for the patients to have own children affected by the disease).

Figure 6

ARPKD can be caused by mutations in different genes. Beyond doubt, the main gene mutated is PKHD1, however, the phenotype is genetically not as homogeneous as often thought. A number of other recessive and dominant genes need to be considered. Most important are dominant and recessive mutations in PKD1 and PKD2, the two genes mainly mutated in patients with adult-onset ADPKD. Other entities that may have to be discussed are HNF1β, novel genes for ARPKD such as DZIP1L and genes that typically cause other cystic kidney diseases and ciliopathies (see main text for details).