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Q&A

Genetics

Poster Session 1

(169) Curating the fetal genome: Experience of the ClinGen Prenatal Gene Curation Expert Panel (GCEP)

Tuesday, February 13, 2024

10:30 AM – 12:00 PM

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

Presenting Author(s)

Stephanie Galloway, MS (she/her/hers)

Assistant Professor of Genetic Counseling
Columbia University
New York, NY, United States

Primary Author(s)

JG

Jessica L. Giordano, MS

Columbia University
New York, NY, United States

Coauthor(s)

AT

Amanda Thomas-Wilson, PhD

New York Genome Center
New York City, NY, United States
VO

Volkan Okur, MD

New York Genome Center
New York City, NY, United States
CS

Carrie J. Shawber, PhD

Columbia University
New York, NY, United States
KG

Kelly L. Gilmore, MS

Instructor, Department of Obstetrics & Gynecology
University of North Carolina at Chapel Hill
Chapel Hill, NC, United States
JR

Julie Ratliff, BS

Broad Institute of MIT and Harvard
Cambridge, MA, United States
Roni Zemet Lazar, MD (she/her/hers)

Assistant Professor
Baylor College of Medicine
Houston, Texas, United States
MG

Mythily Ganapathi, PhD

Columbia University
New York, NY, United States
NC

Natalie Chandler, PhD

North Thames Genomic Laboratory Hub
London, England, United Kingdom
Neeta L. Vora, MD

Associate Professor
University of North Carolina
Chapel Hill, NC, United States
AD

Avinash V. Dharmadhikari, PhD

USC
Los Angeles, CA, United States
JV

Jessica Van Ziffle, PhD

University of California, San Francisco (UCSF)
San Francisco, CA, United States
Teresa N. Sparks, MD (she/her/hers)

Associate Professor, Maternal-Fetal Medicine and Clinical Genetics
University of California, San Francisco (UCSF), School of Medicine
San Francisco, CA, United States
DC

David Chitayat, MD

Head
Mount Sinai Hospital
Toronto, ON, Canada
LC

Lyn Chitty, MD, PhD

Great Ormond Street NHS Foundation Trust
London, England, United Kingdom
ER

Erin Riggs, MS

Geisinger
Lewisburg, PA, United States
AB

Alicia B. Byrne, PhD

Broad Institute of MIT and Harvard
Boston, MA, United States
Ronald J. Wapner, MD (he/him/his)

Professor of OBGYN; Director of Reproductive Genetics
Columbia University Irving Medical Center
New York, NY, United States
WC

Wendy Chung, MD, PhD

Harvard and Boston Children's Hospital
Boston, MA, United States
Ignatia B. Van den Veyver, MD

Professor
Baylor College of Medicine
Houston, TX, United States

Objective: Prenatal genetic diagnosis now includes genomic sequencing. Interpretation of variants is more challenging prenatally than post-natally as fetal phenotypic information is limited to structural/growth abnormalities. Unique fetal phenotypes of genetic diseases and genotype-phenotype associations are underreported, leading to more genes of uncertain significance in the prenatal setting. This uncertainty negatively impacts confidence in reporting prenatal sequencing results by laboratories and the clinical management of pregnancies. To address the limited evidence for prenatal gene-disease associations, we assembled the ClinGen Prenatal GCEP.

Study Design: The initial focus is on genes previously reported as associated with unique prenatal phenotypes: non-immune fetal hydrops (NIHF) and stillbirth (SB). All curators and experts trained in the standardized ClinGen tools to score genetic and functional evidence for gene-disease association. Paired curators and clinical experts focused on one assigned gene. Evidence was reviewed at weekly meetings and published on the ClinGen website.

Results: Genes selected for curation include 151 implicated in NIHF and 221 implicated in SB; 34 overlap between these phenotypes. Pre-curation to assess initial evidence has been completed for 8 genes; primary curation has been completed for 5 genes associated with 7 phenotypes. These include EPHB4, PIEZO1, FLT4, GRIP1, and TUBGCP6, with confirmed causative evidence for hydrops, stillbirth, and prenatally observable fetal anomalies. A secondary curation has been completed for TAFAZZIN; primary curation was done by the Inborn Errors of Metabolism GCEP. Overall, this process has provided international prenatal providers with further clarity about unique fetal features of many genetic diseases, and will translate to more accurate prenatal diagnosis.

Conclusion: Our experience supports the importance of gene curation for prenatal phenotypes. The continuously updated data, which are publicly available online through ClinGen, will significantly facilitate uniformity in diagnostic prenatal sequencing and improve pregnancy management.