Alport syndrome is the second most common genetic cause of chronic kidney disease (CKD) behind autosomal dominant polycystic kidney disease (ADPKD). It has been diagnosed in tens of thousands of Americans, and the classic symptoms include progressive loss of kidney function, sensorineural hearing loss and eye abnormalities. However, the age of onset, severity, rate of progression and risks to individuals can be quite variable, even within the same family. Genetic testing can help providers improve management of individuals with Alport syndrome. Similarly, genetic testing may enable researchers to better understand the mechanisms of this condition and use this knowledge for more personalized medicine.
Genetics of Alport syndrome
Alport syndrome is caused by variants, or mutations, in one of three different collagen genes: COL4A3, COL4A4, or COL4A5. The collagen produced by these genes are important in the formation and integrity of the basement membrane in the glomeruli of the kidney, and also in the ears and eyes. When the basement membranes in these areas are weakened due to structural or functional deficits, symptoms of Alport syndrome develop. In some people, these symptoms could develop in childhood or early adulthood. Others could be asymptomatic into their 70’s. There are several variables that can account for these differences. One of the most important factors is which of the three genes is involved in the Alport syndrome diagnosis.
Alport syndrome is most often caused by variants in COL4A5, which is located on the X chromosome. Since males have only one X chromosome, if they inherit a variant in COL4A5 that causes abnormal collagen, they do not have another working copy to help produce normal collagen. However, females have two X chromosomes, and therefore are able to produce some normal collagen. Males, therefore, have earlier onset of symptoms, and a more severe progression than typically seen in females, who could have normal kidney function even in later adulthood. Men with X-linked Alport syndrome have a 100% chance of developing end-stage kidney disease (ESKD), whereas this risk is less than 25% for women.
COL4A3 and COL4A4 are autosomal genes, meaning that they are located on chromosomes found equally in both males and females. Everyone has two copies of autosomal genes, so the sex of an individual does not impact disease severity as it does with X-linked genes. If an individual has a variant in one copy of their copies of COL4A3 or COL4A4, they may have a range of severity of Alport syndrome, but it is often milder than seen in the X-linked form. This is called autosomal dominant (AD) inheritance. Those who inherit two Alport variants (one on each chromosome) are expected to have severe disease, which is referred to as autosomal recessive (AR) inheritance.
Family risk assessment
Understanding which gene causes Alport syndrome in an individual has important implications for family members. For example, if a 50-year-old man is diagnosed with Alport syndrome due to a COL4A5 (X-linked) variant, and he has three sons, none of his sons would’ve inherited this condition, as sons do not inherit X chromosomes from their father. However, if that same man had three daughters, they all would’ve inherited this variant, and would be at risk for kidney disease themselves, as well as in their children.
There are a number of ways that the inheritance pattern associated with Alport syndrome can affect risks to family members. Genetic counselors can help assess these risks and may also help arrange genetic testing for relatives based on an initial diagnosis.
Clinical Utility of Genetic Testing
Genetic testing for Alport syndrome can be beneficial for an individual in many ways. It may confirm or reclassify a clinical diagnosis. The spectrum of clinical features of Alport syndrome is expanding beyond the classic symptoms to encompass a wider range of presentations, severity and age of onset. Much of this additional understanding is due to genetic testing. As mentioned, genetic testing can provide useful information for family risk assessment. It may also allow the provider to change treatments or medications or make referrals for other possible symptoms. Genetic testing may also allow for enrollment in certain clinical trials aimed at new drug development and validation.
In summary, Alport syndrome is a relatively common, but highly variable, genetic cause of chronic kidney disease. Understanding the underlying genetic cause of CKD can have immense benefits to both a patient and their family. As genetic testing becomes more widespread and cost-effective, more families may better understand the causes of kidney disease. And, as new technologies increase the ability to perform genetic analysis at reasonable cost, researchers and medical professionals will learn more about optimizing healthcare options for individuals with this diagnosis.
