Carrier Status Results for Recessive Disorders

Key Points:

  • A carrier is usually asymptomatic due to having one working and one non-working copy of a gene.
  • There is typically a risk for an affected child when both parents are carriers of the same genetic variant.
  • For X-linked recessive disorders, a female carrier has a risk of having an affected child
  • Carrier status can be discovered in various clinical testing scenarios; testing may be ordered specifically looking for carrier status for reproductive planning or to diagnose a symptomatic individual.

A carrier is an individual who has one working and one non-working copy of a gene. A carrier is capable of passing on a genetic variant associated with recessive disease (autosomal recessive or X-linked recessive) to their offspring. A carrier usually does not display disease symptoms associated with that variant, although in some rare cases a carrier might exhibit some symptoms.

In an individual with a recessive disease, both copies of the gene have variants associated with disease. Autosomal recessive diseases are typically not seen in every generation of an affected family and are equally likely to occur in males and females. One example of an autosomal recessive disease is cystic fibrosis. Both parents of an individual with an autosomal recessive disease likely carry one copy of the altered gene.

Females have two X chromosomes, and males have one X and one Y chromosome. For X-linked conditions, women are typically carriers and have fewer if any symptoms, while males are affected. Males are at an increased risk of disease because they only have one copy of the X chromosome and therefore only one copy of the many genes located on the X chromosome. If one of these genes is not working, there is not another copy to compensate.

A female carrier for an X-linked recessive disease has a 50% chance of passing on the variant in each pregnancy. Sons that inherit the variant would be expected to be affected with the condition, while daughters with the variant are less likely to exhibit symptoms. An example of an X-linked recessive disease is Hemophilia A. A male with an X-linked condition will pass on the variant to each of his daughters (because the variant is on his X chromosome, which he passes on to each female child) and none of his sons (because each son receives only a Y chromosome from his father).

Carrier status can be discovered in a variety of clinical testing scenarios. Tests may be ordered specifically looking for carrier status, identifying people who carry one copy of a gene variant that can be passed on to a child. This type of testing is currently offered to individuals who have a family history of a genetic disease, people in certain ethnic groups with an increased risk of specific genetic diseases (population screening), and people concerned about their risk of having a child with a genetic disease.

All individuals are carriers of multiple genetic diseases. However, rarely are partners having a child both carriers for the same autosomal recessive condition. If couples undergo carrier screening, the test results can provide information about their risk of having a child with a genetic disease. In this scenario the carrier status would be considered a primary result, as it is related to the reason the test was ordered. Carrier testing can be ordered in various ways, including targeted single gene disease testing, panel testing of multiple genetic diseases, or less commonly through a broad genomic test looking for genetic variants throughout the genome or exome.

Carrier status information can be used for reproductive planning and may provide information to other relatives about a possible shared genetic variant. In rare cases when carriers can exhibit symp- toms, a carrier result could inform medical management for the individual being tested.

Example:
A woman has preconception genome sequencing to plan for a future pregnancy. She is found to be a carrier of a pathogenic mutation for cystic fibrosis. Her husband then has genetic testing to see if he is a carrier of the same mutation. He is negative, meaning a cystic fibrosis associated variant was not identified. Based on these results, this couple are very unlikely to have a child with the condition. However children will have a 50% chance of being an unaffected carrier like their mother.

Carrier status can also be revealed as a secondary result, or incidental finding in genomic tests when the primary testing indication is for another reason (e.g., diagnosis of a symptomatic individual) that is unrelated to assessing carrier status. In this case the carrier result may be relevant to the patient, siblings, parents, or other relatives for future reproductive planning. As above, in some rare cases in which carriers exhibit symptoms, a carrier result could inform medical management.

Limitations
There are some important limitations to be aware of when interpreting carrier results from a genomic test. Carrier testing is a screening test. If one has a negative carrier test result, there is still a residual risk of being a carrier due to the possibility of a genetic variant that was not detected or reported. Sequencing does not identify all types of variants. This limitation means that the most common variants for some well-known and commonly tested for diseases such as spinal muscular atrophy (SMA) and Fragile X cannot reliably be detected by NGS. In addition, many laboratories do not routinely report variants of uncertain significance (VUS) related to carrier status results. An individual may still be a carrier of (or affected with) a disease if no variants or only one variant is found in the relevant gene.

Some variants (and associated genetic diseases) are more common in certain ethnic groups, due to a single genetic variant or set of common genetic variants within that population. However, variants in all genes can occur in any population. It is important to note whether a test interrogates a set of common variants, or sequences entire genes (and identifies both common and rare variants). This, as well as the carrier frequency within the patient’s specific population group, is important when determining risk related to a negative result.

A carrier for a recessive condition is asymptomatic and has a pathogenic genetic variant in just one of their two copies of the associated gene. Parents that are both carriers of the same recessive condition have a 25% chance that a child will inherit the pathogenic variant from both parents and be affected with the condition. There is a 50% chance that the child will inherit a single pathogenic variant from one parent and will also be an asymptomatic carrier. There is a 25% chance that the child will inherit neither variant and will not be affected or a carrier.

A carrier for a recessive condition is asymptomatic and has a pathogenic genetic variant in just one of their two copies of the associated gene. Parents that are both carriers of the same recessive condition have a 25% chance that a child will inherit the pathogenic variant from both parents and be affected with the condition. There is a 50% chance that the child will inherit a single pathogenic variant from one parent and will also be an asymptomatic carrier. There is a 25% chance that the child will inherit neither variant and will not be affected or a carrier.

 

Next Steps to Consider

  • Learn more about the recessive condition with which the patient has been diagnosed through GeneReviews, OMIM and other resources
  • Referral to genetic services (medical geneticist and/or genetic counselor) for in-depth discussion of reproductive risks and implications for family members
  • Carrier testing of patient’s partner for the specific gene/genetic condition identified to further clarify risk of having a child with the recessive disorder

 

Resources

  • GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1116/): a resource for clinicians that provide clinically relevant and medically actionable information for inherited condition. This resource includes information on diagnostic criteria, management, and information about genetic counseling for patients and their families. There are chapters available about many, but not all, genetic conditions.
  • National Society of Genetic Counselors (http://nsgc.org/): the professional organization for genetic counselors, with patient and provider resources and a searchable tool to “find a genetic counselor” near you.