Alport syndrome

Alport syndrome can be inherited in three different ways. About 80 percent of cases are caused by mutations in the COL4A5 gene and are inherited in an X-linked recessive pattern. The COL4A5 gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the COL4A5 gene in each cell is sufficient to cause kidney failure and other severe symptoms of the disorder. In females (who have two X chromosomes), a mutation in only one copy of the COL4A5 gene usually only results in hematuria. However, some women experience more severe symptoms such as kidney failure or hearing loss. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.^[1]

In approximately 15 percent of cases, Alport syndrome results from mutations in both copies of the COL4A3 or COL4A4 gene and is inherited in an autosomal recessive pattern. The parents of an individual with the autosomal recessive form of this condition each have one copy of the mutated gene and are called carriers. Some carriers are unaffected, and others develop a less severe condition called thin basement membrane nephropathy, which is characterized by hematuria. Males and females are equally affected by the autosomal recessive form of Alport syndrome.^[1]

Alport syndrome is rarely inherited as an autosomal dominant condition. People with this form of Alport syndrome have one mutation in either COL4A3 or COL4A4 in each cell. It remains unclear why some individuals with one mutation in the COL4A3 or COL4A4 gene have autosomal dominant Alport syndrome and others have thin basement membrane nephropathy or no symptoms at all.^[1][2]

Males with a disease-causing mutation in a gene on the X chromosome will typically be affected with the associated condition if it is known to have 100% penetrance. In males (who have only one X chromosome), a disease-causing mutation in their one copy of the COL4A5 gene in each cell is sufficient to cause the signs and symptoms of X-linked Alport syndrome. This means that an unaffected male with a family history of X-linked Alport syndrome is assumed to not be a carrier of the condition. Males who are not carriers are not at risk to pass the condition on to their children.

Whether the maternal female cousins of a male with X-linked Alport syndrome (XLAS) are at risk to be carriers of the condition depends on whether the mother of the affected individual is a carrier. In a family with more than one affected male, the mother of an affected individual is an obligate carrier. If only one male in a family is affected, the likelihood that that individual's mother is a carrier is estimated to be 85%-90%. Approximately 10%-15% of affected males have XLAS as the result of a de novo mutation (a new mutation occurring for the first time in that individual).^[3] A de novo mutation is not usually inherited from a parent; therefore, in these cases, cousins are typically not at increased risk.

The mother of a male with XLAS should have a urinalysis and/or molecular genetic testing if the mutation has been identified in her son. The presence of hematuria generally indicates that she is likely to be a carrier of XLAS.^[3] If the mother of an affected male is indeed a carrier of XLAS, the maternal female cousins are also at risk to be carriers of XLAS. Whether their children are at risk would likewise depend on whether they are carriers.

Individuals interested in learning about specific genetic risks to themselves or family members should speak with a genetics professional.

No. If a woman is not a carrier for X-linked Alport syndrome (XLAS), she does not have the disease-causing mutation; therefore, her sons are not at risk for being affected and her daughters are not at risk to be carriers. This means that her grandchildren are also not at risk to be affected or to be carriers for XLAS.

If the mutation has been identified in an affected male, the mother of the affected male can have a urinalysis and/or molecular genetic testing. The presence of hematuria (blood in the urine) generally indicates that she is likely to be a carrier of XLAS; molecular genetic testing can confirm whether she is a carrier. If the family history indicates risk to other family members, urinalysis and/or molecular genetic testing may be informative for them as well.^[3]

Individuals interested in determining the genetic risk and status for themselves or family members should speak with a genetics professional to determine whether they are at risk and/or the type of testing that is indicated.

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.