title: Identification of Symptomatic Fetuses Infected with Cytomegalovirus Using Amniotic Fluid Peptide Biomarkers.
abstract: Cytomegalovirus (CMV) is the most common cause of congenital infection, and is a major cause of sensorineural hearing loss and neurological disabilities. Evaluating the risk for a CMV infected fetus to develop severe clinical symptoms after birth is crucial to provide appropriate guidance to pregnant women who might have to consider termination of pregnancy or experimental prenatal medical therapies. However, establishing the prognosis before birth remains a challenge. This evaluation is currently based upon fetal imaging and fetal biological parameters, but the positive and negative predictive values of these parameters are not optimal, leaving room for the development of new prognostic factors. Here, we compared the amniotic fluid peptidome between asymptomatic fetuses who were born as asymptomatic neonates and symptomatic fetuses who were either terminated in view of severe cerebral lesions or born as severely symptomatic neonates. This comparison allowed us to identify a 34-peptide classifier in a discovery cohort of 13 symptomatic and 13 asymptomatic neonates. This classifier further yielded 89% sensitivity, 75% specificity and an area under the curve of 0.90 to segregate 9 severely symptomatic from 12 asymptomatic neonates in a validation cohort, showing an overall better performance than that of classical fetal laboratory parameters. Pathway analysis of the 34 peptides underlined the role of viral entry in fetuses with severe brain disease as well as the potential importance of both beta-2-microglobulin and adiponectin to protect the injured fetal brain infected with CMV. The results also suggested the mechanistic implication of the T calcium channel alpha-1G (CACNA1G) protein in the development of seizures in severely CMV infected children. These results open a new field for potential therapeutic options. In conclusion, this study demonstrates that amniotic fluid peptidome analysis can effectively predict the severity of congenital CMV infection. This peptidomic classifier may therefore be used in clinical settings during pregnancy to improve prenatal counseling.
authors.affiliation: Department of Obstetrics and Fetal Medicine, Hospital Necker-Enfants-Malade, APHP, Paris, France.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Desveaux
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institute of Cardiovascular and Metabolic Disease, Toulouse, France.|Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Klein
authors.affiliation: Department of Virology, Hospital Necker-Enfants Malades, AP-HP, Paris, France.|University Paris Descartes, EA 7328, Paris, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Leruez-Ville
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America.
authors.forename: Adela
authors.initials: A
authors.lastname: Ramirez-Torres
authors.affiliation: Université Toulouse III Paul-Sabatier, Toulouse, France.|Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Lacroix
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institute of Cardiovascular and Metabolic Disease, Toulouse, France.|Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Breuil
authors.affiliation: Université Toulouse III Paul-Sabatier, Toulouse, France.|Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Froment
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institute of Cardiovascular and Metabolic Disease, Toulouse, France.|Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Jean-Loup
authors.initials: JL
authors.lastname: Bascands
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institute of Cardiovascular and Metabolic Disease, Toulouse, France.|Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Joost P
authors.initials: JP
authors.lastname: Schanstra
authors.affiliation: Department of Obstetrics and Fetal Medicine, Hospital Necker-Enfants-Malade, APHP, Paris, France.|University Paris Descartes, EA 7328, Paris, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Ville
mesh_terms: D000649:Amniocentesis; D000653:Amniotic Fluid / Q000821:virology*; D019540:Area Under Curve; D015415:Biomarkers / Q000032:analysis*; D003586:Cytomegalovirus Infections / Q000175:diagnosis* / Q000635:transmission; D005260:Female; D005315:Fetal Diseases / Q000175:diagnosis* / Q000821:virology; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D010455:Peptides / Q000032:analysis; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000175:diagnosis*; D012372:ROC Curve; D012680:Sensitivity and Specificity; D014764:Viral Proteins / Q000032:analysis
chemical_list: D015415:Biomarkers; D010455:Peptides; D014764:Viral Proteins