Androgen insensitivity syndrome

Having a variant in the AR gene (androgen receptor), which causes androgen insensitivity syndrome (AIS), means that a variation, or a genetic change has been found in an individual. When a gene is sequenced, to check for a change, it is compared to a 'reference genomic sequence'. This means that the DNA in question is compared to "normal" DNA, or DNA that we know does not have a change in the AIS gene.

Not all variants in the AR gene cause androgen insensitivity syndrome. Variants are classified into one of three categories: benign, variant of unknown significance (VUS), or pathogenic.

Benign variants are changes that do not cause the disease. These changes can be seen in people without AIS. These benign changes are usually seen at a fairly high frequency among the general population. If a benign variant is found, this is not the reason for an individual's AIS.

Variants of uncertain significance are changes that have not been seen enough before in the general population, or in people with AIS to determine if it is causing the disease. In other words, these changes are uncertain. These variants may or may not be causing AIS. Further studies may have to be done to determine if these variants are causing AIS, such as skin biopsy to check functionality. Usually, with time, variants of uncertain significance are reclassified as pathogenic or benign, as they are seen more frequently in individuals with AIS or in individuals in the general population. Medical management changes are rarely made based on a variant of uncertain significance.

Pathogenic variants are changes that are known to cause the disease. These changes have been seen in people with AIS and have not been seen in the general population at a high frequency. If a pathogenic variant is found, this is usually the reason for an individual's AIS.

For further clarification on variants, please contact your doctor or a genetic counselor. Genetic counselors can be found on the National Society of Genetic Counselors website.

Newborn screening is a state run program that screens babies at birth for certain serious medical conditions. There is no newborn screening offered for androgen insensitivity syndrome.

If there is concern for AIS in a newborn, a special test can be ordered for that baby.

For further information about newborn screening, talk with your doctor or a genetic counselor. Genetic counselors can be found on the National Society of Genetic Counselors website.

Prenatal testing is available if there are known mutations in the family. Androgen insensitivity syndrome (AIS) mutations must be confirmed through genetic testing of the AR (androgen receptor) gene in the carrier mother or other affected family member. Testing of the fetus during pregnancy is done by a chorionic villus sampling (CVS) or amniocentesis. Before pregnancy, preimplantation genetic diagnosis (PGD) with in vitro fertilization (IVF) can be pursued. PGD with IVF involves a process in which embryos can be genetically tested and only the embryos without a mutation can be implanted.

Genetic counselors can be a resource for more information about testing before or during pregnancy. Genetic counselors can be found on the National Society of Genetic Counselors website.

Complete androgen insensitivity syndrome (AIS) is typically diagnosed based on clinical and laboratory findings, and can be further confirmed with genetic testing. However, a family history and genetic testing can also help in the diagnosis of partial and mild AIS.

The AR (androgen receptor) is the only gene in which genetic changes, called mutations, are known to cause androgen insensitivity syndrome. As a result, genetic testing of the AR gene code (sequence analysis, as well as gene deletion/duplication) can be done to look for mutations and can be used to confirm AIS.

Typically, it is a physical presentation of genitalia (sex organs) that first alerts a doctor to consider a diagnosis of AIS. If an AR gene mutation is not identified doctors may wish to pursue other multi-gene panel tests which include genes for similar disorders. If a gene mutation is still not identified, but AIS is still being considered, doctors may wish to perform a skin biopsy to test the functioning of the androgen receptor in the skin.

For more information about the genetic testing process, speak with a medical geneticist or genetic counselor. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website.

Traditionally, molecular genetic testing of the AR (androgen receptor) gene for androgen insensitivity syndrome (AIS) uses blood. However, saliva or skin biopsy can also be used. DNA can be extracted from either type of sample. Different laboratories will have different requirements. It is best to know laboratory requirements before sending a sample.

If a child is diagnosed with androgen insensitivity syndrome (AIS) and a genetic change, called a mutation, in the AR (androgen receptor) gene has confirmed the diagnosis, testing the mother is an important next step. If the mother is tested, and she is a carrier this can help determine the risk to other family members, such as siblings and extended family members. Carriers have the same mutation and can pass on the mutation to other family members but usually do not present with characteristics of AIS. There are some carriers, though, that will have very mild symptoms. These are called 'manifesting carriers'.

It is important to remember that fathers pass on the Y chromosome to their son's, not an X chromosome. Since the AR gene is located on the X chromosome, this is why mothers are tested and not fathers.

Siblings and other at risk family members can pursue genetic testing to determine if they have a form of AIS or are carriers. However, testing should be considered in addition to any physical characteristics that may suggest AIS. A detailed family history can also provide information about which family members are at risk for developing AIS and could consider genetic testing.

To learn more about who in your family should be tested, talk with a genetic counselor. Genetic counselors can be found on the National Society of Genetic Counselors website.