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Q&A

Genetics

Poster Session 1

(234) Expanded carrier screening for genetic conditions with clinical trials in-utero therapy

Tuesday, February 13, 2024

10:30 AM – 12:00 PM

Location: Prince George's Exhibit Hall CDE, Lower Atrium Level

Presenting Author(s)

Billie R. Lianoglou, MS (she/her/hers)

Genetic Counselor
University of California, San Francisco (UCSF), Center for Maternal-Fetal Precision Medicine
San Francisco, CA, United States

Coauthor(s)

Vivienne Souter, MD

Research Director, Obstetrical Care Outcomes Assessment Program
Foundation for Health Care Quality
Seattle, WA, United States
BP

Brittany Prigmore, MS

Natera, Inc.
Austin, TX, United States
ER

Elizabeth Repass, MS

Natera, Inc.
Austin, TX, United States
YW

Yang Wang, PhD

Natera, Inc.
Austin, TX, United States

Primary Author(s)

Tippi C. MacKenzie, MD

Professor of Surgery, John G. Bowes Distinguished Professor in Stem Cell and Tissue Biology, Director, The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Co-Director, Center for Maternal-Fetal Precision Medicine
University of California, San Francisco (UCSF), Center for Maternal-Fetal Precision Medicine
San Francisco, CA, United States

Objective: Molecular fetal therapies for monogenetic conditions are an emerging area of care with the potential to transform outcomes. Identifying pregnancies eligible for treatment is challenging for conditions with no ultrasound manifestations. We evaluated carrier frequency for 9 conditions identifiable through reproductive carrier screening, focusing on conditions with active in-utero (IU) clinical trials.

Study Design: This retrospective observational study included carrier screening tests from female patients, aged 18-55 years, ordered from a US commercial laboratory (Jan 2020-Sept 2022). Samples were tested for a variety of panels ranging from 2 to 421 genes. We calculated the proportion of samples that included screening for any of the conditions with IU therapy trials and the gene-specific carrier frequency for 7 autosomal recessive (AR) conditions and 2 X-linked (XL) conditions (Table 1). To focus on severe subtypes eligible for IU therapy, we excluded pseudodeficiency variants in IDUA, GAA, and ARSB and the neuronopathic protective variant (p.N409S) of Gaucher disease.

Results: Of 822,155 samples screened, 228,720 (28%) were for a panel that included none of the conditions and were excluded from the analysis. 15,237 (1.9%) were for a panel with all of the relevant conditions with clinical trials of IU therapy. For the 7 AR conditions, the carrier frequency ranged from 1 in 77 for Pompe disease (GAA) to 1 in 1693 for MPS VII (GUSB) (Table 1). For the XL conditions, the carrier frequency was 1 in 5580 for X-linked Hypohidrotic Ectodermal Dysplasia (EDA) and 1 in 19274 for Hunter syndrome (IDS).

Conclusion: Our study highlights that carriers for these individually “rare” conditions are, collectively, not uncommon. However, many patients have screening with panels that detect none of the conditions and few have panels that detect all. As fetal and early postnatal treatment options expand for rare genetic conditions, we should reconsider the paradigm of screening (currently based on carrier frequency) to also include conditions with actionable findings.