Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis
Teresa N Sparks, Billie R Lianoglou, Rebecca R Adami, Ilina D Pluym, Kerry Holliman, Jennifer Duffy, Sarah L Downum, Sachi Patel, Amanda Faubel, Nina M Boe, Nancy T Field, Aisling Murphy, Louise C Laurent, Jennifer Jolley, Cherry Uy, Anne M Slavotinek, Patrick Devine, Ugur Hodoglugil, Jessica Van Ziffle, Stephan J Sanders, Tippi C MacKenzie, Mary E Norton, University of California Fetal–Maternal Consortium, University of California, San Francisco Center for Maternal–Fetal Precision Medicine, Teresa N Sparks, Billie R Lianoglou, Rebecca R Adami, Ilina Datkhaeva, Kerry Holliman, Jennifer Duffy, Sarah L Downum, Sachi Patel, Amanda Faubel, Nina M Boe, Nancy T Field, Aisling Murphy, Louise C Laurent, Jennifer Jolley, Cherry Uy, Anne M Slavotinek, Patrick Devine, Ugur Hodoglugil, Jessica Van Ziffle, Stephan J Sanders, Tippi C MacKenzie, Mary E Norton, Nina Boe, Erin Brown, Diana Farmer, Nancy Field, Hedriana Herman, Shinjiro Hirose, Gina James, Elyse Love, Amelia McLennan, Francis Poulain, Amy Powne, Laila Rhee Morris, Catherine Rottkamp, Payam Saadai, Sherzana Sunderji, Veronique Tache, Jay Yeh, M Baraa Allaf, Katie Bacca, Lisa Carroll, Brian Crosland, Robert Day, David Gibbs, Afshan Hameed, Tamara Hatfield, Alexandra Iacob, Mustafa Kabeer, Nafiz Kiciman, Nancy Lee, Carol Major, Joshua Makhoul, Yona Nicolau, Manuel Porto, Rebecca Post, Lizette Spiers, Melissa Westermann, Peter Yu, Irfan Ahmad, Nita Doshi, Yigit Guner, Wyman Lai, Pierangelo Renella, Yalda Afshar, Kara Calkins, Judith Chung, Daniel DeUgarte, Uday Devaskar, Jaime Deville, Viviana Fajardo, Meena Garg, Rachel Gutkin, Christina Han, Carla Janzen, Howard Jen, Suhas Kallapur, Steven Lee, Steven Lerman, Melanie Maykin, Tina Nguyen, Victoria Niklas, Naseem Rangwala, Rashmi Rao, Animesh Sabnis, Gary Satou, Emily Scibetta, Mark Sklansky, Rebecca Stark, Katie Strobel, Renea Sturm, Khalil Tabsh, Thalia Wong, Rebecca Adami, Tracy Anton, Jerasimos Ballas, Stephen Bickler, Erika Fernandez, Andrew Hull, Marni Jacobs, Diana Johnson, Karen Kling, Leah Lamale-Smith, Sarah Lazar, Louise Laurent, Dora Melber, Mana Parast, Mishella Perez, Dolores Pretorius, Sandy Ramos, Maryam Tarsa, Douglas Woelkers, Kathy Zhang-Rutledge, Kirsten Drummer, Ian Fraser Golding, Laurel Moyer, Heather Sun, Kathryn Archbold, Victoria Berger, Paul Brakeman, Melissa Catenacci, Shilpa Chetty, Hillary Copp, Valerie Dougherty, Sarah Downum, Vickie Feldstein, Marla Ferschl, Neda Ghaffari, Ruth Goldstein, Juan Gonzalez-Velez, Veronica Gonzalez, Kristen Gosnell, Michael Harrison, Whitnee Hogan, Romobia Hutchinson, Roxanna Irani, Priyanka Jha, Roberta Keller, Katelin Kramer, Hanmin Lee, Billie Lianoglou, Jennifer Lucero, Tippi MacKenzie, Anne Mardy, Erin Matsuda, Edward Miller, Anita Moon-Grady, Tara Morgan, Amy Murtha, Mary Norton, Natalie Oman, Benjamin Padilla, Shabnam Peyandi, Andrew Phelps, Liina Poder, Annalisa Post, Larry Rand, Diana Robles, Frederico Rocha, Melissa Rosenstein, Janice Scudmore, Dorothy Shum, Nasim Sobhani, Teresa Sparks, Katherine Swanson, Martha Tesfalul, Stephanie Gaw, Lan Vu, Amanda Yeaton-Massey, James Anderson, Lisa Arcilla, Erin Corbett, Erna Josiah-Davis, Leslie Lusk, Howard Rosenfeld, Teresa N Sparks, Billie R Lianoglou, Rebecca R Adami, Ilina D Pluym, Kerry Holliman, Jennifer Duffy, Sarah L Downum, Sachi Patel, Amanda Faubel, Nina M Boe, Nancy T Field, Aisling Murphy, Louise C Laurent, Jennifer Jolley, Cherry Uy, Anne M Slavotinek, Patrick Devine, Ugur Hodoglugil, Jessica Van Ziffle, Stephan J Sanders, Tippi C MacKenzie, Mary E Norton, University of California Fetal–Maternal Consortium, University of California, San Francisco Center for Maternal–Fetal Precision Medicine, Teresa N Sparks, Billie R Lianoglou, Rebecca R Adami, Ilina Datkhaeva, Kerry Holliman, Jennifer Duffy, Sarah L Downum, Sachi Patel, Amanda Faubel, Nina M Boe, Nancy T Field, Aisling Murphy, Louise C Laurent, Jennifer Jolley, Cherry Uy, Anne M Slavotinek, Patrick Devine, Ugur Hodoglugil, Jessica Van Ziffle, Stephan J Sanders, Tippi C MacKenzie, Mary E Norton, Nina Boe, Erin Brown, Diana Farmer, Nancy Field, Hedriana Herman, Shinjiro Hirose, Gina James, Elyse Love, Amelia McLennan, Francis Poulain, Amy Powne, Laila Rhee Morris, Catherine Rottkamp, Payam Saadai, Sherzana Sunderji, Veronique Tache, Jay Yeh, M Baraa Allaf, Katie Bacca, Lisa Carroll, Brian Crosland, Robert Day, David Gibbs, Afshan Hameed, Tamara Hatfield, Alexandra Iacob, Mustafa Kabeer, Nafiz Kiciman, Nancy Lee, Carol Major, Joshua Makhoul, Yona Nicolau, Manuel Porto, Rebecca Post, Lizette Spiers, Melissa Westermann, Peter Yu, Irfan Ahmad, Nita Doshi, Yigit Guner, Wyman Lai, Pierangelo Renella, Yalda Afshar, Kara Calkins, Judith Chung, Daniel DeUgarte, Uday Devaskar, Jaime Deville, Viviana Fajardo, Meena Garg, Rachel Gutkin, Christina Han, Carla Janzen, Howard Jen, Suhas Kallapur, Steven Lee, Steven Lerman, Melanie Maykin, Tina Nguyen, Victoria Niklas, Naseem Rangwala, Rashmi Rao, Animesh Sabnis, Gary Satou, Emily Scibetta, Mark Sklansky, Rebecca Stark, Katie Strobel, Renea Sturm, Khalil Tabsh, Thalia Wong, Rebecca Adami, Tracy Anton, Jerasimos Ballas, Stephen Bickler, Erika Fernandez, Andrew Hull, Marni Jacobs, Diana Johnson, Karen Kling, Leah Lamale-Smith, Sarah Lazar, Louise Laurent, Dora Melber, Mana Parast, Mishella Perez, Dolores Pretorius, Sandy Ramos, Maryam Tarsa, Douglas Woelkers, Kathy Zhang-Rutledge, Kirsten Drummer, Ian Fraser Golding, Laurel Moyer, Heather Sun, Kathryn Archbold, Victoria Berger, Paul Brakeman, Melissa Catenacci, Shilpa Chetty, Hillary Copp, Valerie Dougherty, Sarah Downum, Vickie Feldstein, Marla Ferschl, Neda Ghaffari, Ruth Goldstein, Juan Gonzalez-Velez, Veronica Gonzalez, Kristen Gosnell, Michael Harrison, Whitnee Hogan, Romobia Hutchinson, Roxanna Irani, Priyanka Jha, Roberta Keller, Katelin Kramer, Hanmin Lee, Billie Lianoglou, Jennifer Lucero, Tippi MacKenzie, Anne Mardy, Erin Matsuda, Edward Miller, Anita Moon-Grady, Tara Morgan, Amy Murtha, Mary Norton, Natalie Oman, Benjamin Padilla, Shabnam Peyandi, Andrew Phelps, Liina Poder, Annalisa Post, Larry Rand, Diana Robles, Frederico Rocha, Melissa Rosenstein, Janice Scudmore, Dorothy Shum, Nasim Sobhani, Teresa Sparks, Katherine Swanson, Martha Tesfalul, Stephanie Gaw, Lan Vu, Amanda Yeaton-Massey, James Anderson, Lisa Arcilla, Erin Corbett, Erna Josiah-Davis, Leslie Lusk, Howard Rosenfeld
Abstract
Background: The cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear.
Methods: We evaluated a series of 127 consecutive unexplained cases of NIHF that were defined by the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or a combination of these conditions. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited.
Results: In 37 of the 127 cases (29%), we identified diagnostic genetic variants, including those for disorders affecting the RAS-MAPK cell-signaling pathway (known as RASopathies) (30% of the genetic diagnoses); inborn errors of metabolism and musculoskeletal disorders (11% each); lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders (8% each); and others. Prognoses ranged from a relatively mild outcome to death during the perinatal period. Overall, 68% of the cases (25 of 37) with diagnostic variants were autosomal dominant (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was of uncertain inheritance. We identified potentially diagnostic variants in an additional 12 cases.
Conclusions: In this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases. (Funded by the UCSF Center for Maternal-Fetal Precision Medicine and others; ClinicalTrials.gov number, NCT03412760.).
Copyright © 2020 Massachusetts Medical Society.
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Source: PubMed