Carrier Testing

Beth N. PeshkinCases

Case

Luciana, age 29, and her husband, Malik, age 32, want to start a family. Malik’s brother has cystic fibrosis (CF). Luciana and Malik sent their DNA to a direct-to-consumer company, 23andMe, which tested for 28 variants in the CFTR gene. The couple was delighted that no mutations were identified in this or any other gene for which testing was performed.

CAN THEY BE REASSURED ABOUT THEIR RISK FOR HAVING A CHILD WITH CF?

The diagnosis of CF needs to be confirmed in Malik’s brother, and it is important to know which two CFTR mutations he has. Without knowing which mutations are present in Malik’s brother, it is not possible to provide complete reassurance to the couple about their risk of having a child with CF.

Cystic fibrosis is an autosomal recessive condition, meaning that, with rare exception, both parents must carry a mutation in the CFTR gene in order to have an affected child. When both parents are mutation carriers, there is a 25% chance they will have a child affected with CF.

According to the 23andMe website, testing is performed for 28 mutations in the CFTR gene. These include 21 of 23 mutations recommended by the American College of Medical Genetics and Genomics. Testing is most sensitive for individuals of European, Hispanic/Latino, and Ashkenazi Jewish descent. Luciana is Hispanic, and Malik’s family is African. Thus, it is very possible that his affected brother has mutations that are not on this panel.

WHAT IF MALIK CANNOT FIND OUT HIS BROTHER’S GENETIC STATUS?

Malik would need to have his CFTR gene sequenced.

If no information about Malik’s brother is available, then Malik would need to have his CFTR gene sequenced. There are over 1700 mutations in the CFTR gene. If he is not a carrier, then the couple is not at-risk for having a child with CF, and there is no need to sequence Luciana’s CFTR gene. If he is a carrier for a mutation identified on sequencing, then if that specific is ruled out in Luciana with additional testing, the couple is not at risk for having a child affected with CF. (However, their child could be a CF carrier.)

In addition, it is important to take a full family history from Luciana and Malik to make sure that they are not at risk for any other inherited conditions or chromosomal abnormalities.

SHOULD I EVER RECOMMEND THAT MY PATIENTS GET CARRIER TESTING THROUGH A DTC COMPANY?

Probably not.

When decisions around pregnancy and the health of future children are at stake, DTC testing is not a substitute for comprehensive genetic counseling and clinical testing. Sometimes patients pursue DTC testing because it is a cheaper option than clinical testing and because they can bypass genetic counseling. This case exemplifies the potential risks associated with improper interpretation of DTC results. Moreover, not all DTC labs are created equal, so if your patients choose to pursue DTC testing, it is important that they understand the potential limitations, and that additional confirmatory testing may be recommended.

I DON’T THINK I WILL SEE A CASE LIKE THIS. WHAT CAN I TAKE AWAY FROM THIS EXAMPLE?

Testing the affected individual first is usually recommended before testing at-risk relatives.

This case raises two important themes in genomic medicine. The first is that genomic testing is not a substitute for risk assessment based on family history. Both are important. Both have limitations. But each plays an important role.

The second theme is that when a hereditary condition is suspected or reported by a patient, confirming the diagnosis is often necessary. If you cannot obtain verification of a reported condition, it is important to document that in your clinic notes. Further, testing the affected individual first (before testing at-risk relatives), is usually recommended. Doing so usually facilitates result interpretation for relatives.

Credits

Images
baby – https://unsplash.com/photos/Bi4szXGcCAM

Shimojima, Keiko, et al. “Whole-exome sequencing identifies a de novo TUBA1A mutation in a patient with sporadic malformations of cortical development: a case report.” BMC research notes 7.1 (2014): 465. — CC by Attribution. Image cropped and tinted for display.

References

American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 486: Update on carrier screening for cystic fibrosis. Obstet Gynecol 2011;117:1028-31. Available at: http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Genetics/Update-on-Carrier-Screening-for-Cystic-Fibrosis

Moskowitz SM, Chmiel JF, Sternen DL, et al. CFTR-Related Disorders. 2001 Mar 26 [Updated 2008 Feb 19]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1250/