Carrier screening began 50 years ago with screening for conditions that have a high prevalence in defined racial/ethnic groups (e.g., Tay–Sachs disease in the Ashkenazi Jewish population; sickle cell disease in Black individuals). Cystic fibrosis was the first medical condition for which panethnic screening was recommended, followed by spinal muscular atrophy. Next-generation sequencing allows low cost and high throughput identification of sequence variants across many genes simultaneously. Since the phrase “expanded carrier screening” is nonspecific, there is a need to define carrier screening processes in a way that will allow equitable opportunity for patients to learn their reproductive risks using next-generation sequencing technology. An improved understanding of this risk allows patients to make informed reproductive decisions. Reproductive decision making is the established metric for clinical utility of population-based carrier screening. Furthermore, standardization of the screening approach will facilitate testing consistency. This practice resource reviews the current status of carrier screening, provides answers to some of the emerging questions, and recommends a consistent and equitable approach for offering carrier screening to all individuals during pregnancy or preconception.
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The authors would like to thank the members of the American College of Medical Genetics and Genomics who spent their time reading this document, considering its implications and for their suggested edits.
M.A., N.T.L., M.T.B. and E.C. are directors of molecular testing laboratories that offer carrier screening. J.S.D. is a member of the Advisory Board for Informed DNA and Medical Co-Director at Insight Medical Genetics in Chicago, which provides genetic laboratory services. The other authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This practice resource is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this practice resource is completely voluntary and does not necessarily assure a successful medical outcome. This practice resource should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.
Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this practice resource. Clinicians also are advised to take notice of the date this practice resource was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.
The Board of Directors of the American College of Medical Genetics and Genomics approved this practice resource on 12 April 2021.
The original online version of this article was revised: Several factual errors were made on the original version of this manuscript. The authors regret the errors.
On p6: ACMG Recommends: All pregnant patients and those planning a pregnancy should be offered Tier 3 carrier screening for autosomal recessive (Tables 1–5) and X-linked (Table 6) conditions. Reproductive partners of pregnant patients and those planning a pregnancy may be offered Tier 3 carrier screening for autosomal recessive conditions (Tables 1–5) when carrier screening is performed simultaneously with their pregnant partner.
First paragraph of p 10: The possibility of manifesting heterozygotes and their associated clinical features, if such are known, as in cases of carriers of X-linked conditions (for example, cardio- myopathy in DMD carriers; primary ovarian failure in FMR1 premutation carriers) should be discussed as part of pretest counseling.
On p 10 last paragraph: Carrier screening counseling should be provided by knowledgeable and appropriately trained health-care professionals and should be performed pre- and post-test. It should be noted that traditional models of genetic counseling can be both time and labor intensive. Thus, new models need to be developed and instituted for both training nongenetics providers and counseling patients. These models might include videos, chatbots, computer-based learning, or other methods of providing information to patients and assessing their understanding. Carrier screening for autosomal recessive conditions is unique when compared to other medical testing in that test results impact the likelihood of offspring of the patient having a genetic condition, while for the most part, the patient screened is healthy. However, patients with two X chromosomes, who screen positive for X-linked conditions may manifest symptoms of the condition (e.g., OTC deficiency and hemophilia) because of skewed X inactivation. This also explains why some carriers of Duchenne muscular dystrophy (DMD) or Fabry disease (GLA) experience cardiomyopathy. A subset of these patients who have a FMR1 premutation allele are at risk to develop premature ovarian insufficiency, a condition unrelated to that seen in their XY offspring (i.e., fragile X syndrome).
Bottom of p 11: When sequential screening is performed and one partner is discovered to be a carrier of an autosomal recessive or X-linked condition, that partner should undergo counseling by a knowledgeable and appropriately trained health- care professional. In specific circumstances, it may be especially appropriate to seek the assistance of a genetics professional, for example (1) when the gene or variant is known to be associated with variable expressivity, (2) when an X-linked carrier is identified, (3) when autosomal recessive carriers of gene variants that have possible phenotypic implications are identified, and (4) when a VUS is disclosed.
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Gregg, A.R., Aarabi, M., Klugman, S. et al. Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med 23, 1793–1806 (2021). https://doi.org/10.1038/s41436-021-01203-z
European Journal of Human Genetics (2021)