Polycystic kidney disease (PKD) is a progressive, inherited disorder characterized by the growth of numerous fluid-filled sacs, called cysts, within the kidneys. The presence of these cysts enlarges the kidneys over time, interfering with their ability to filter waste products from the blood. Understanding the genetic basis of PKD is important because it dictates the disease’s progression, severity, and the inheritance risk for future generations.
Understanding Polycystic Kidney Disease
PKD involves the development of cyst clusters originating from the renal tubules, the tiny tubes responsible for forming urine. These cysts are essentially non-functioning tubules that fill with fluid and vary widely in size. As they grow, the cysts compress and destroy surrounding healthy kidney tissue, leading to the gradual loss of kidney function over many years. This process eventually results in end-stage renal disease (ESRD), requiring dialysis or a kidney transplant for survival. PKD is the most common inherited kidney disorder and a significant cause of kidney failure globally.
The Two Primary Forms of Inheritance
Polycystic kidney disease is categorized into two main forms based on inheritance pattern: Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Autosomal Recessive Polycystic Kidney Disease (ARPKD). The vast majority of cases are ADPKD, affecting an estimated 1 in 400 to 1,000 people. ADPKD follows a dominant inheritance pattern, meaning a person needs only one copy of the mutated gene from either parent to develop the condition.
If one parent has ADPKD, their children have a 50% chance of inheriting the altered gene and developing the disease. The disease does not skip generations; if the gene is not inherited, the child cannot pass it on. Symptoms of ADPKD typically appear in adulthood, often between the ages of 30 and 50, though cysts may be present from birth or childhood.
The much rarer form is Autosomal Recessive Polycystic Kidney Disease (ARPKD), occurring in approximately 1 in 20,000 live births. Recessive inheritance requires a child to receive two copies of the mutated gene, one from each parent, to develop the disease. Parents who carry only one copy of the mutated gene are typically healthy and are referred to as carriers.
When two carrier parents conceive a child, there is a 25% chance the child will develop ARPKD by inheriting two mutated copies. There is a 50% chance the child will become a carrier, and a 25% chance they will inherit two normal copies. ARPKD is typically much more severe than the dominant form, with symptoms often apparent at birth or in early infancy, sometimes leading to life-threatening complications.
Genetic Basis: The Specific Genes Involved
The different forms of PKD are linked to specific gene mutations that affect protein production involved in the structure and function of the kidney’s tubules. ADPKD is primarily caused by mutations in two genes: PKD1 and PKD2. The PKD1 gene, located on chromosome 16, is responsible for approximately 85% of ADPKD cases and encodes polycystin-1 (PC1).
The PKD2 gene, located on chromosome 4, accounts for the remaining 15% of cases and encodes polycystin-2 (PC2). PC1 and PC2 form a complex that functions as a mechanosensory receptor and a calcium-permeable ion channel, primarily located on the primary cilia of renal tubular cells. Mutations disrupt the signaling pathway that regulates cell growth, differentiation, and fluid secretion, leading to uncontrolled cell proliferation and cyst formation.
A PKD1 mutation is associated with a more severe disease course, with patients often progressing to end-stage renal failure around age 55. In contrast, PKD2 mutations typically result in a milder form and later onset of kidney failure, often around age 74. Cyst formation for both genes follows a “two-hit” mechanism: the inherited mutation (first hit) is followed by a spontaneous somatic mutation (second hit) in a specific kidney cell, which then triggers cyst growth.
Autosomal Recessive PKD is caused by mutations in the PKHD1 gene, located on chromosome 6. This gene provides instructions for making fibrocystin, also known as polyductin. Fibrocystin is a large protein found in the primary cilia and basal body of renal and bile duct epithelial cells.
Similar to polycystins, fibrocystin is believed to play a role in regulating cell proliferation and maintaining the correct structure of the renal tubules. PKHD1 mutations lead to defective fibrocystin, resulting in characteristic cyst development in the kidneys and often fibrosis in the liver. The severity of ARPKD is often related to the specific PKHD1 mutation type, with certain truncating mutations resulting in the most severe, often lethal, outcomes.
Genetic Screening and Family Planning
For families with a known history of PKD, genetic screening assesses risk and aids in informed family planning decisions. Genetic testing identifies specific gene mutations (PKD1, PKD2, or PKHD1), confirming diagnosis and providing prognostic information. While diagnosis often relies on imaging tests like ultrasound, genetic testing is helpful when the diagnosis is unclear or when determining the precise genetic variant.
Genetic counseling provides detailed information about inheritance patterns and the probability of passing the condition to children. For couples who wish to ensure their children do not inherit PKD, preimplantation genetic testing for monogenic disorders (PGT-M) is available. This process involves creating embryos through in vitro fertilization (IVF), testing them for the familial PKD mutation, and implanting only those that do not carry the gene.
PGT-M allows families to proactively break the cycle of inheritance, though this is a complex and personal decision. For women with ADPKD who choose natural conception, pregnancy is considered higher risk, requiring close monitoring due to potential complications like high blood pressure. Open discussion with a healthcare team, including a genetic counselor, is recommended to evaluate the risks and benefits of all available options.