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Pan-ethnic carrier screening is replacing ethnicity-based carrier screening for single gene disorders

For 50 years, identifying heterozygotes has made possible prevention of selected autosomal recessive disorders. If an asymptomatic individual is a heterozygote and his or her partner likewise there is 25% risk for any given offspring to have that genetic disorder. Risk can be known before pregnancy. Original carrier screening programs targeted Tay-Sachs disease in individuals of Ashkenazi Jewish ancestry. One in 25 Ashkenazi Jewish individuals are heterozygotes for Tay-Sachs disease. Testing took advantage of the enzyme (gene product) hexosaminidase A being quantitatively less in carrier than in homozygous* normal individuals. Protein-based screening was the only possible approach at that time because DNA-based testing did not become realistic until the 2000s.

Other original carrier screening programs begun in the 1970s were for hemoglobinopathies(34). One in 12 individuals of African or African-American origin are carriers for sickle cell anemia (i.e., sickle cell trait).  Diagnosis relied upon hemoglobin electrophoresis. The one other hemoglobinopathy able to be screened at that time was β-thalassemia, prevalent among Greeks, Italians (Sicilians), Turks, Arabs, Southern Iranians, and Asian Indians. Carrier detection for β-thalassemia was based on presence of anemia that is not due to iron deficiency and is accompanied by a mean corpuscular volume less than 80 fL (microcytosis). Until the past decade, few additional disorders could be screened. The only exceptions were a few Ashkenazi Jewish disorders in which only a limited number of causative mutants accounted for over 90-95% of carriers, making it practical to test for these DNA variants.

Expanded DNA-based Pan-ethnic Carrier Screening

In the last decade, ethnicity-based carrier screening as previously practiced has become largely replaced by pan-ethnic screening. Couples consisting of different ethnicities are eligible. The American College of Obstetricians and Gynecologists (ACOG) explicitly states that “ethnic-specific, pan-ethnic, and expanded carrier screening are acceptable strategies for pregnancy and prenatal carrier screening” (ACOG No 691 Obstetrics Gynecology 129; e35-e40).  Mutations responsible for hundreds of disorders can now be screened for carrier status by interrogating their DNA. There is no consensus on the number of disorders screened. In one study, the most common 18 disorders screened account for 84% of at-risk couples identified, whereas screening for 73 additional disorders added only 11% (Ben Shacher et al. Genet Med 2019:21:1313-19).

With pan-ethnic screening increasing the number of disorders, a different approach to genetic counseling is needed compared to that provided with ethnicity-based screening. In ethnicity-based screening the phenotype of each disorder to be screened can be patiently explained, and couples allowed to decide whether they do or do not wish to be screened for that disorder. This is practical if the number of disorders is limited. With pan-ethnic DNA screening for 400 disorders, such as approach is unrealistic. Alternative approaches must be devised, such as providing details only on disorders for which a couple has been shown to be at 1 in 4 risk.

Despite complexities, the benefit of DNA-based expanded carrier screening is well established. In a 2018 report Hogan et al (Clin Chem 2018; 8: 64-67) reported that 1 in 22 couples would be at risk for a detectable disorder; 1 in 300 fetuses would be affected. Results vary among platforms, but one expects approximately 2% of couples to be at risk for an autosomal recessive disorder.  Of relevance to reproductive medicine and IVF units, PGT-M is often preferred for prenatal genetic diagnosis by an at-risk couple. An unaffected embryo can be identified and transferred. If the option of natural conception is chosen, followed by invasive prenatal procedures (amniocentesis; chorionic villus sampling), a clinical pregnancy termination may be necessary to avoid an affected liveborn.

By: Joe Leigh Simpson, MD, FACMG, FACOG, FRCOG