Prenatal care has long included carrier screening for genetic diseases, such as cystic fibrosis and Tay-Sachs disease. Recently, advances in genetics technologies led to the development of multiplex panels that can be used to test for hundreds of genetic disorders simultaneously, and can be used to assess carrier status for expectant couples or those planning a pregnancy. Although such screening covers many more conditions than those recommended in traditional guidelines, the benefit of expanded carrier screening (ECS) over standard gene-by-gene testing is not clear.
In this Update, I review recent ECS research that can be helpful to those who practice reproductive endocrinology and infertility medicine, maternal–fetal medicine, and general ObGyn. This research considered some of the many complexities of ECS:
- number and type of severe autosomal recessive conditions identified by an ECS panel, or by panethnic screening for 3 common conditions (cystic fibrosis, fragile X syndrome, spinal muscular atrophy)
- whether the disorders covered by ECS panels meet recommended criteria regarding severity, prevalence, and test accuracy
- women’s thoughts and perspectives on ECS
- whether the marketing materials disseminated by commercial providers of ECS are accurate and balanced.
Genetic diseases identified by expanded carrier screening
Haque IS, Lazarin GA, Kang HP, Evans EA, Goldberg JD, Wapner RJ. Modeled fetal risk of genetic diseases identified by expanded carrier screening. JAMA. 2016;316(7):734-742.
Screening during pregnancy to determine if one or both parents are carriers of genetic disorders historically has involved testing for a limited number of conditions, such as cystic fibrosis, hemoglobinopathies, and Tay-Sachs disease. Patients usually are offered testing for 1 or 2 disorders, with test choices primarily based on patient race and ethnicity. Unfortunately, ancestry-based screening may result in inequitable distribution of genetic testing and resources, as it has significant limitations in our increasingly multicultural society, which includes many people of uncertain or mixed race and ethnicity.
Advantages of expanded carrier screening
Several commercial laboratories now offer ECS. Haque and colleagues used data from one of these laboratories and modeled the predicted number of potentially affected fetuses that would be identified with traditional, ethnicity-based screening as compared with ECS. In one of their hypothetical cohorts, of Northern European couples, traditional screening would identify 55 affected fetuses per 100,000 (1 in 1,800), and ECS would identify 159 per 100,000 (almost 3 times more). The numbers identified with ECS varied with race or ethnicity and ranged from 94 per 100,000 (about 1 in 1,000) for Hispanic couples to 392 per 100,000 (about 1 in 250) for Ashkenazi Jewish couples.
In Australia, Archibald and colleagues conducted a similar study, of panethnic screening of 12,000 women for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy.1 The number of affected fetuses identified was about 1 per 1,000 screened couples--not much different from the ECS number, though comparison is difficult given the likely very different racial and ethnic backgrounds of the 2 cohorts.
Although these data suggest ECS increases detection of genetic disorders, and it seems almost self-evident that more screening is better, there are concerns about ECS.2 Traditional carrier screening methods focus on conditions that significantly affect quality of life--owing to cognitive or physical disabilities or required lifelong medical therapies--and that have a fetal, neonatal, or early-childhood onset and well-defined phenotype. In ECS panels, additional conditions may vary significantly in severity or age of onset. Although some genetic variants on ECS panels have a consistent phenotype, the natural history of others is less well understood. Panels often include conditions for which carrier screening of the general population is not recommended by current guidelines--for example, hemochromatosis and factor V Leiden. Moreover, almost by definition, ECS panels include rare conditions for which the natural history may not be well understood, and the carrier frequency as well as the proportion of condition-causing variants that can be detected may be unclear, leaving the residual risk unknown.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
This study provides additional information on the number and type of conditions that can be detected with ECS in different populations. Although ever larger panels can detect more conditions, the veracity of the results and the types of conditions detected are important considerations as providers and patients weigh the risks and benefits of this screening.