Modeled Fetal Risk of Genetic Diseases Identified by Expanded Carrier Screening

Abstract

IMPORTANCE Screening for carrier status of a limited number of single-gene conditions is the current standard of prenatal care. Methods have become available allowing rapid expanded carrier screening for a substantial number of conditions. OBJECTIVES To quantify the modeled risk of recessive conditions identifiable by an expanded carrier screening panel in individuals of diverse racial and ethnic backgrounds and to compare the results with those from current screening recommendations. DESIGN, SETTING, AND PARTICIPANTS Retrospective modeling analysis of results between January 1, 2012, and July 15, 2015, from expanded carrier screening in reproductive-aged individuals without known indication for specific genetic testing, primarily from the United States. Tests were offered by clinicians providing reproductive care. EXPOSURES Individuals were tested for carrier status for up to 94 severe or profound conditions. MAIN OUTCOMES AND MEASURES Risk was defined as the probability that a hypothetical fetus created from a random pairing of individuals (within or across 15 self-reported racial/ethnic categories; there were 11 categories with >5000 samples) would be homozygous or compound heterozygous for 2 mutations presumed to cause severe or profound disease. Severe conditions were defined as those that if left untreated cause intellectual disability or a substantially shortened lifespan; profound conditions were those causing both. RESULTS The study included 346 790 individuals. Among major US racial/ethnic categories, the calculated frequency of fetuses potentially affected by a profound or severe condition ranged from 94.5 per 100 000 (95% CI, 82.4-108.3 per 100 000) for Hispanic couples to 392.2 per 100 000 (95% CI, 366.3-420.2 per 100 000) for Ashkenazi Jewish couples. In most racial/ethnic categories, expanded carrier screening modeled more hypothetical fetuses at risk for severe or profound conditions than did screening based on current professional guidelines (Mann-Whitney P < .001). For Northern European couples, the 2 professional guidelines-based screening panels modeled 55.2 hypothetical fetuses affected per 100 000 (95% CI, 51.3-59.3 per 100 000) and the expanded carrier screening modeled 159.2 fetuses per 100 000 (95% CI, 150.4-168.6 per 100 000). Overall, relative to expanded carrier screening, guideline-based screening ranged from identification of 6% (95% CI, 4%-8%) of hypothetical fetuses affected for East Asian couples to 87% (95% CI, 84%-90%) for African or African American couples. CONCLUSIONS AND RELEVANCE In a population of diverse races and ethnicities, expanded carrier screening may increase the detection of carrier status for a variety of potentially serious genetic conditions compared with current recommendations from professional societies. Prospective studies comparing current standard-of-care carrier screening with expanded carrier screening in at-risk populations are warranted before expanded screening is adopted.

Implementation of a Carrier Screening Program in a High-Risk Undergraduate Student Population Using Digital Marketing, Online Education, and Telehealth

“…In traditional models, discussion of available testing options and screening often occur in an obstetrician’s office, and males and preconception patients are less likely to be reached. Based on a study of over 346,000 patients screened by Counsyl Laboratory, approximately 79% of individuals undergoing routine carrier screening were female [17]; this population may not be representative of the numbers found in screening programs since most of the reported Counsyl tests were ordered by obstetricians or other reproductive specialists. In this college initiative, 56% of participants were female, which is similar to the overall JScreen program in which approximately 55% of participants are female.…”

“…The diseases included on the screening panel were selected by the laboratory based on disease severity, actionability, prevalence, and ability to reliably identify carriers [16, 17]. Pathogenicity of variants was determined by the laboratory according to ACMG guidelines [17].…”

“…Pathogenicity of variants was determined by the laboratory according to ACMG guidelines [17]. The disease list suggested by the laboratory was then evaluated and culled by the JScreen genetic counselors and approved by the program’s medical genetics director.…”

Obstetric management, tests, and technologies that impact childhood development

“…Compared to current recommendations from the American College of Obstetricians and Gynecologists and the American College of Medical Genetics and Genomics, expanded carrier screening detected at least twice as many hypothetical fetuses at risk in all ethnic categories, with the exception of African or African-American and Southeast Asian. 16 Despite an apparent benefit, the need for genetic counseling remains paramount and one must consider the hidden costs of expanded carrier screening. Current US-based commercial laboratories offering expanded carrier screening do not test for the same genetic conditions.…”

Associations of perceived norms with intentions to learn genomic sequencing results: Roles for attitudes and ambivalence.

“…Advancements in sequencing technology have reduced the cost and increased availability of testing (Biesecker & Green, 2014). Genomic sequencing can be used to identify the cause of undiagnosed disease (Daoud et al, 2016), to test for medically actionable secondary findings (Green et al, 2013), and for broad carrier screening (Haque et al, 2016). Results from genomic sequencing can be particularly useful in the case of actionable results, to reduce future health risks by pursuing screening or changing one’s lifestyle behaviors, and in carrier screening, to make informed reproductive choices.…”