TY - JOUR
T1 - Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death
AU - Broad Institute Center for Mendelian Genomics
AU - Genomic Autopsy Study Research Network
AU - Byrne, Alicia B.
AU - Arts, Peer
AU - Ha, Thuong T.
AU - Kassahn, Karin S.
AU - Pais, Lynn S.
AU - O’Donnell-Luria, Anne
AU - Aguet, François
AU - Arachchi, Harindra M.
AU - Austin-Tse, Christina A.
AU - Babb, Larry
AU - Baxter, Samantha M.
AU - Brand, Harrison
AU - Chang, Jaime
AU - Chao, Katherine R.
AU - Collins, Ryan L.
AU - Cummings, Beryl
AU - Delano, Kayla
AU - DiTroia, Stephanie P.
AU - England, Eleina
AU - Evangelista, Emily
AU - Everett, Selin
AU - Francioli, Laurent C.
AU - Fu, Jack
AU - Ganesh, Vijay S.
AU - Garimella, Kiran V.
AU - Gauthier, Laura D.
AU - Goodrich, Julia K.
AU - Gudmundsson, Sanna
AU - Hall, Stacey J.
AU - Huang, Yongqing
AU - Jahl, Steve
AU - Laricchia, Kristen M.
AU - Larkin, Kathryn E.
AU - Lek, Monkol
AU - Lemire, Gabrielle
AU - Lipson, Rachel B.
AU - Lovgren, Alysia Kern
AU - MacArthur, Daniel G.
AU - Mangilog, Brian E.
AU - Mano, Stacy
AU - Marshall, Jamie L.
AU - Mullen, Thomas E.
AU - Nguyen, Kevin K.
AU - O’Heir, Emily
AU - O’Leary, Melanie C.
AU - Osei-Owusu, Ikeoluwa A.
AU - de Acha Chavez, Jorge Perez
AU - Pierce-Hoffman, Emma
AU - Gecz, Jozef
AU - Perez-Jurado, Luis A.
N1 - Funding Information:
First, we thank the families for their involvement in our project. We thank the Genomic Autopsy Study Research Network, which includes the referring clinical geneticists, genetic counselors, pathologists, colleagues at research and diagnostic laboratories and Australian Genomics, for their assistance with patient care, contributions and support. Additional thanks to the staff of the Kinghorn Centre for Clinical Genomics Sequencing Laboratory, the staff of the Centre for Cancer Biology ACRF Genomics Facility and the staff of the Broad Institute’s Genomic Platform. This research was supported by NHMRC (grant no. APP1123341), Genomics Health Futures Mission – Medical Research Futures Fund (no. GHFM76777) and the Australian Genomic Health Alliance NHMRC Targeted Call for Research into Preparing Australia for the Genomics Revolution in Healthcare (no. GNT1113531) to H.S.S. and C.P.B.; and by the ACRF to H.S.S. Sequencing provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) was funded by the National Human Genome Research Institute, the National Eye Institute and the National Heart, Lung and Blood Institute (grant no. UM1 HG008900 to D.G.M. and H.L.R). Additional support was provided by Cancer Council SA’s Beat Cancer Project on behalf of its donors and the State Government of South Australia through the Department of Health, and NHMRC Fellowship (no. APP1023059) to H.S.S.; by the Australian Government Research Training Program Scholarship, the Australian Genomics Health Alliance PhD Award & NHMRC (no. GNT1113531) and by the Maurice de Rohan International Scholarship (to A.B.B.). P.A.was supported by fellowships from the The Hospital Research Foundation and the Royal Adelaide Hospital Research Fund.
Publisher Copyright:
© 2023, Crown.
PY - 2023/1
Y1 - 2023/1
N2 - Pregnancy loss and perinatal death are devastating events for families. We assessed ‘genomic autopsy’ as an adjunct to standard autopsy for 200 families who had experienced fetal or newborn death, providing a definitive or candidate genetic diagnosis in 105 families. Our cohort provides evidence of severe atypical in utero presentations of known genetic disorders and identifies novel phenotypes and disease genes. Inheritance of 42% of definitive diagnoses were either autosomal recessive (30.8%), X-linked recessive (3.8%) or autosomal dominant (excluding de novos, 7.7%), with risk of recurrence in future pregnancies. We report that at least ten families (5%) used their diagnosis for preimplantation (5) or prenatal diagnosis (5) of 12 pregnancies. We emphasize the clinical importance of genomic investigations of pregnancy loss and perinatal death, with short turnaround times for diagnostic reporting and followed by systematic research follow-up investigations. This approach has the potential to enable accurate counseling for future pregnancies.
AB - Pregnancy loss and perinatal death are devastating events for families. We assessed ‘genomic autopsy’ as an adjunct to standard autopsy for 200 families who had experienced fetal or newborn death, providing a definitive or candidate genetic diagnosis in 105 families. Our cohort provides evidence of severe atypical in utero presentations of known genetic disorders and identifies novel phenotypes and disease genes. Inheritance of 42% of definitive diagnoses were either autosomal recessive (30.8%), X-linked recessive (3.8%) or autosomal dominant (excluding de novos, 7.7%), with risk of recurrence in future pregnancies. We report that at least ten families (5%) used their diagnosis for preimplantation (5) or prenatal diagnosis (5) of 12 pregnancies. We emphasize the clinical importance of genomic investigations of pregnancy loss and perinatal death, with short turnaround times for diagnostic reporting and followed by systematic research follow-up investigations. This approach has the potential to enable accurate counseling for future pregnancies.
UR - http://www.scopus.com/inward/record.url?scp=85146557041&partnerID=8YFLogxK
U2 - 10.1038/s41591-022-02142-1
DO - 10.1038/s41591-022-02142-1
M3 - Article
C2 - 36658419
AN - SCOPUS:85146557041
SN - 1078-8956
VL - 29
SP - 180
EP - 189
JO - Nature Medicine
JF - Nature Medicine
IS - 1
ER -