Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death

Alicia B. Byrne; Peer Arts; Thuong T. Ha; Karin S. Kassahn; Lynn S. Pais; Anne O’Donnell-Luria; Broad Institute Center for Mendelian Genomics; Milena Babic; Mahalia S.B. Frank; Jinghua Feng; Paul Wang; David M. Lawrence; Leila Eshraghi; Luis Arriola; John Toubia; Hung Nguyen; Genomic Autopsy Study Research Network; Andrew Dubowsky; Eric A. Haan; Chirag Patel; George McGillivray; Jason Pinner; Fiona McKenzie; Rebecca Morrow; Jill Lipsett; Nick Manton; T. Yee Khong; Lynette Moore; Jan E. Liebelt; Andreas W. Schreiber; Sarah L. King-Smith; Tristan S.E. Hardy; Matilda R. Jackson; Christopher P. Barnett; Hamish S. Scott

doi:10.1038/s41591-022-02142-1

Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death

Alicia B. Byrne, Peer Arts, Thuong T. Ha, Karin S. Kassahn, Lynn S. Pais, Anne O’Donnell-Luria, Broad Institute Center for Mendelian Genomics, Milena Babic, Mahalia S.B. Frank, Jinghua Feng, Paul Wang, David M. Lawrence, Leila Eshraghi, Luis Arriola, John Toubia, Hung Nguyen, Genomic Autopsy Study Research Network, Andrew Dubowsky, Eric A. Haan, Chirag PatelGeorge McGillivray, Jason Pinner, Fiona McKenzie, Rebecca Morrow, Jill Lipsett, Nick Manton, T. Yee Khong, Lynette Moore, Jan E. Liebelt, Andreas W. Schreiber, Sarah L. King-Smith, Tristan S.E. Hardy, Matilda R. Jackson, Christopher P. Barnett, Hamish S. Scott

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	180-189
Number of pages	10
Journal	NATURE MEDICINE
Volume	29
Issue number	1
DOIs	https://doi.org/10.1038/s41591-022-02142-1
Publication status	Published - Jan 2023
Externally published	Yes

Keywords

Disease genetics
Genetic testing
Medical genomics

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10.1038/s41591-022-02142-1Licence: CC BY

Final published versionFinal published version, 8.76 MBLicence: CC BY

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Byrne, A. B., Arts, P., Ha, T. T., Kassahn, K. S., Pais, L. S., O’Donnell-Luria, A., Broad Institute Center for Mendelian Genomics, Babic, M., Frank, M. S. B., Feng, J., Wang, P., Lawrence, D. M., Eshraghi, L., Arriola, L., Toubia, J., Nguyen, H., Genomic Autopsy Study Research Network, Dubowsky, A., Haan, E. A., ... Scott, H. S. (2023). Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death. NATURE MEDICINE, 29(1), 180-189. https://doi.org/10.1038/s41591-022-02142-1

@article{583b0872d54442afbe9448af2231e83f,

title = "Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death",

abstract = "Pregnancy loss and perinatal death are devastating events for families. We assessed {\textquoteleft}genomic autopsy{\textquoteright} 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.",

keywords = "Disease genetics, Genetic testing, Medical genomics",

author = "Byrne, {Alicia B.} and Peer Arts and Ha, {Thuong T.} and Kassahn, {Karin S.} and Pais, {Lynn S.} and Anne O{\textquoteright}Donnell-Luria and {Broad Institute Center for Mendelian Genomics} and Fran{\c c}ois Aguet and Arachchi, {Harindra M.} and Austin-Tse, {Christina A.} and Larry Babb and Baxter, {Samantha M.} and Harrison Brand and Jaime Chang and Chao, {Katherine R.} and Collins, {Ryan L.} and Beryl Cummings and Kayla Delano and DiTroia, {Stephanie P.} and Eleina England and Emily Evangelista and Selin Everett and Francioli, {Laurent C.} and Jack Fu and Ganesh, {Vijay S.} and Garimella, {Kiran V.} and Gauthier, {Laura D.} and Goodrich, {Julia K.} and Sanna Gudmundsson and Hall, {Stacey J.} and Yongqing Huang and Steve Jahl and Laricchia, {Kristen M.} and Larkin, {Kathryn E.} and Monkol Lek and Gabrielle Lemire and Lipson, {Rachel B.} and Lovgren, {Alysia Kern} and MacArthur, {Daniel G.} and Mangilog, {Brian E.} and Stacy Mano and Marshall, {Jamie L.} and Mullen, {Thomas E.} and Nguyen, {Kevin K.} and Emily O{\textquoteright}Heir and O{\textquoteright}Leary, {Melanie C.} and Osei-Owusu, {Ikeoluwa A.} and {de Acha Chavez}, {Jorge Perez} and Emma Pierce-Hoffman and Rehm, {Heidi L.} and Jillian Serrano and Moriel Singer-Berk and Hana Snow and Matthew Solomonson and Son, {Rachel G.} and Abigail Sveden and Michael Talkowski and Grace Tiao and Udler, {Miriam S.} and Zaheer Valivullah and Elise Valkanas and VanNoy, {Grace E.} and Wang, {Qingbo S.} and Watts, {Nicholas A.} and Ben Weisburd and Williamson, {Clara E.} and Wilson, {Michael W.} and Lauren Witzgall and Wojcik, {Monica H.} and Isaac Wong and Wood, {Jordan C.} and Shifa Zhang and Milena Babic and Frank, {Mahalia S.B.} and Jinghua Feng and Paul Wang and Lawrence, {David M.} and Leila Eshraghi and Luis Arriola and John Toubia and Hung Nguyen and {Genomic Autopsy Study Research Network} and Disna Abeysuriya and Ades, {Lesley C.} and Amor, {David J.} and Susan Arbuckle and Madhura Bakshi and Bligh Berry and Tiffany Boughtwood and Adam Bournazos and Alessandra Bray and Fiona Chan and Yuen Chan and Clara Chung and Jonathan Clark and Jackie Collett and Alison Colley and Felicity Collins and Sandra Cooper and Corbett, {Mark A.} and Dahlstrom, {Jane E.} and Peter Dargaville and Janene Davies and Tenielle Davis and Jarrad Dearman and Jayanthi Dissanayake and Julia Dobbins and Helen Doyle and Andrew Dubowsky and Matt Edwards and Ewans, {Lisa J.} and Mitali Fadia and Andrew Fennell and Keri Finlay and Andrew French and Kathryn Friend and Gardner, {Alison E.} and Jozef Gecz and Nicole Graf and Haan, {Eric A.} and Georgina Hollingsworth and Horton, {Ari E.} and Denise Howting and Hunter, {Matthew F.} and Gareth Jevon and Benjamin Kamien and Debra Kennedy and Michael Krivanek and Thessa Kroes and Krzesinski, {Emma I.} and Edward Kwan and Stephanie Lau and Shannon LeBlanc and Suzanna Lindsey-Temple and Loo, {Christine K.C.} and Julia Low and Amali Mallawaarachchi and Admire Matsika and Tessa Mattiske and Julie McGaughran and Lesley McGregor and Namita Mittal and Ali Moghimi and Albayrak, {Hatice Mutlu} and Jessica Ng and Jillian Nicholl and Nicholas Pachter and John Papadimitriou and Renae Parker and Sarah Parsons and Chirag Patel and Rhonda Pawlowski and Perez-Jurado, {Luis A.} and Katerina Politis and Cathryn Poulton and Theresa Power and Michael Quinn and Sulekha Rajagopalan and Matthew Regan and Jonathan Rodgers and Steuart Rorke and Rani Sachdev and Suzanne Sallevelt and Sandaradura, {Sarah A.} and Maryam Shamassi and Roshan Shamon and Isabella Sherburn and Jennie Slee and Annalisa Solinas and Ella Sugo and Elizabeth Thompson and Sagarika Tripathy and Anand Vasudevan and Melisa Vazquez and Kunal Verma and Mthulisi Viki and Mathew Wallis and Webber, {Dani L.} and Martin Weber and Karen Whale and Meredith Wilson and Lisa Worgan and Sui Yu and George McGillivray and Jason Pinner and Fiona McKenzie and Rebecca Morrow and Jill Lipsett and Nick Manton and Khong, {T. Yee} and Lynette Moore and Liebelt, {Jan E.} and Schreiber, {Andreas W.} and King-Smith, {Sarah L.} and Hardy, {Tristan S.E.} and Jackson, {Matilda R.} and Barnett, {Christopher P.} and Scott, {Hamish S.}",

year = "2023",

month = jan,

doi = "10.1038/s41591-022-02142-1",

language = "English",

volume = "29",

pages = "180--189",

journal = "NATURE MEDICINE",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "1",

}

Byrne, AB, Arts, P, Ha, TT, Kassahn, KS, Pais, LS, O’Donnell-Luria, A, Broad Institute Center for Mendelian Genomics, Babic, M, Frank, MSB, Feng, J, Wang, P, Lawrence, DM, Eshraghi, L, Arriola, L, Toubia, J, Nguyen, H, Genomic Autopsy Study Research Network, Dubowsky, A, Haan, EA, Patel, C, McGillivray, G, Pinner, J, McKenzie, F, Morrow, R, Lipsett, J, Manton, N, Khong, TY, Moore, L, Liebelt, JE, Schreiber, AW, King-Smith, SL, Hardy, TSE, Jackson, MR, Barnett, CP & Scott, HS 2023, 'Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death', NATURE MEDICINE, vol. 29, no. 1, pp. 180-189. https://doi.org/10.1038/s41591-022-02142-1

TY - JOUR

T1 - Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death

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 - Broad Institute Center for Mendelian Genomics

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 - Rehm, Heidi L.

AU - Serrano, Jillian

AU - Singer-Berk, Moriel

AU - Snow, Hana

AU - Solomonson, Matthew

AU - Son, Rachel G.

AU - Sveden, Abigail

AU - Talkowski, Michael

AU - Tiao, Grace

AU - Udler, Miriam S.

AU - Valivullah, Zaheer

AU - Valkanas, Elise

AU - VanNoy, Grace E.

AU - Wang, Qingbo S.

AU - Watts, Nicholas A.

AU - Weisburd, Ben

AU - Williamson, Clara E.

AU - Wilson, Michael W.

AU - Witzgall, Lauren

AU - Wojcik, Monica H.

AU - Wong, Isaac

AU - Wood, Jordan C.

AU - Zhang, Shifa

AU - Babic, Milena

AU - Frank, Mahalia S.B.

AU - Feng, Jinghua

AU - Wang, Paul

AU - Lawrence, David M.

AU - Eshraghi, Leila

AU - Arriola, Luis

AU - Toubia, John

AU - Nguyen, Hung

AU - Genomic Autopsy Study Research Network

AU - Abeysuriya, Disna

AU - Ades, Lesley C.

AU - Amor, David J.

AU - Arbuckle, Susan

AU - Bakshi, Madhura

AU - Berry, Bligh

AU - Boughtwood, Tiffany

AU - Bournazos, Adam

AU - Bray, Alessandra

AU - Chan, Fiona

AU - Chan, Yuen

AU - Chung, Clara

AU - Clark, Jonathan

AU - Collett, Jackie

AU - Colley, Alison

AU - Collins, Felicity

AU - Cooper, Sandra

AU - Corbett, Mark A.

AU - Dahlstrom, Jane E.

AU - Dargaville, Peter

AU - Davies, Janene

AU - Davis, Tenielle

AU - Dearman, Jarrad

AU - Dissanayake, Jayanthi

AU - Dobbins, Julia

AU - Doyle, Helen

AU - Dubowsky, Andrew

AU - Edwards, Matt

AU - Ewans, Lisa J.

AU - Fadia, Mitali

AU - Fennell, Andrew

AU - Finlay, Keri

AU - French, Andrew

AU - Friend, Kathryn

AU - Gardner, Alison E.

AU - Gecz, Jozef

AU - Graf, Nicole

AU - Haan, Eric A.

AU - Hollingsworth, Georgina

AU - Horton, Ari E.

AU - Howting, Denise

AU - Hunter, Matthew F.

AU - Jevon, Gareth

AU - Kamien, Benjamin

AU - Kennedy, Debra

AU - Krivanek, Michael

AU - Kroes, Thessa

AU - Krzesinski, Emma I.

AU - Kwan, Edward

AU - Lau, Stephanie

AU - LeBlanc, Shannon

AU - Lindsey-Temple, Suzanna

AU - Loo, Christine K.C.

AU - Low, Julia

AU - Mallawaarachchi, Amali

AU - Matsika, Admire

AU - Mattiske, Tessa

AU - McGaughran, Julie

AU - McGregor, Lesley

AU - Mittal, Namita

AU - Moghimi, Ali

AU - Albayrak, Hatice Mutlu

AU - Ng, Jessica

AU - Nicholl, Jillian

AU - Pachter, Nicholas

AU - Papadimitriou, John

AU - Parker, Renae

AU - Parsons, Sarah

AU - Patel, Chirag

AU - Pawlowski, Rhonda

AU - Perez-Jurado, Luis A.

AU - Politis, Katerina

AU - Poulton, Cathryn

AU - Power, Theresa

AU - Quinn, Michael

AU - Rajagopalan, Sulekha

AU - Regan, Matthew

AU - Rodgers, Jonathan

AU - Rorke, Steuart

AU - Sachdev, Rani

AU - Sallevelt, Suzanne

AU - Sandaradura, Sarah A.

AU - Shamassi, Maryam

AU - Shamon, Roshan

AU - Sherburn, Isabella

AU - Slee, Jennie

AU - Solinas, Annalisa

AU - Sugo, Ella

AU - Thompson, Elizabeth

AU - Tripathy, Sagarika

AU - Vasudevan, Anand

AU - Vazquez, Melisa

AU - Verma, Kunal

AU - Viki, Mthulisi

AU - Wallis, Mathew

AU - Webber, Dani L.

AU - Weber, Martin

AU - Whale, Karen

AU - Wilson, Meredith

AU - Worgan, Lisa

AU - Yu, Sui

AU - McGillivray, George

AU - Pinner, Jason

AU - McKenzie, Fiona

AU - Morrow, Rebecca

AU - Lipsett, Jill

AU - Manton, Nick

AU - Khong, T. Yee

AU - Moore, Lynette

AU - Liebelt, Jan E.

AU - Schreiber, Andreas W.

AU - King-Smith, Sarah L.

AU - Hardy, Tristan S.E.

AU - Jackson, Matilda R.

AU - Barnett, Christopher P.

AU - Scott, Hamish S.

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.

KW - Disease genetics

KW - Genetic testing

KW - Medical genomics

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 -

Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death

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