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)

Abstract

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.

Fig. 1. The Euler diagram shows an overlapping tiered approach to carrier screening.

*Recommended by the American College of Medical Genetics and Genomics (ACMG)^, and American College of Obstetricians and Gynecologists (ACOG). ^±Recommended by ACOG. ^§Supported by literature.^{, ¥}Offered by molecular testing laboratories; the list of genes/conditions may vary by the laboratory. CF cystic fibrosis, SMA spinal muscular atrophy.

Fig. 2. The criterion used to generate the list of genes recommended for screening in Tables 1-6 are shown.

Criterion for genes listed in Tables 1-4 were identical and derive from gnomAD. Those genes listed in Table 5 do not derive from gnomAD data. The X-linked conditions derive from the OMIM database. The prevalence data for X-linked conditions derives from either OMIM, Orphanet, or MedlinePlus. All conditions were at least moderately severe.^, OMIM Online Mendelian Inheritance in Man.