Mark W Russell1, Julie S Moldenhauer2, Jack Rychik3, Nancy B Burnham4, Erin Zullo4, Samuel I Parry5, Rebecca A Simmons6, Michal A Elovitz5, Susan C Nicolson7, Rebecca L Linn8, Mark P Johnson2, Sunkyung Yu9, Matthew G Sampson10, Hakon Hakonarson11, J William Gaynor4. 1. Division of Pediatric Cardiology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI. Electronic address: mruss@med.umich.edu. 2. Center for Fetal Diagnosis and Therapy, The Children's Hospital of Philadelphia, Philadelphia, PA. 3. Division of Pediatric Cardiology, The Children's Hospital of Philadelphia, Philadelphia, PA. 4. Division of Cardiothoracic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA. 5. Division of Maternal Fetal Medicine, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA. 6. Division of Neonatology, The Children's Hospital of Philadelphia, Philadelphia, PA. 7. Division of Cardiothoracic Anesthesiology, The Children's Hospital of Philadelphia, Philadelphia, PA. 8. Division of Anatomic Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA. 9. Division of Pediatric Cardiology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI. 10. Division of Pediatric Nephrology, Department of Pediatrics, and Center for Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI. 11. The Center for Applied Genomics, The Children's Hospital of Philadelphia and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Abstract
OBJECTIVE: To determine the impact of damaging genetic variation in proangiogenic pathways on placental function, complications of pregnancy, fetal growth, and clinical outcomes in pregnancies with fetal congenital heart defect. STUDY DESIGN: Families delivering a baby with a congenital heart defect requiring surgical repair in infancy were recruited. The placenta and neonate were weighed and measured. Hemodynamic variables were recorded from a third trimester (36.4 ± 1.7 weeks) fetal echocardiogram. Exome sequencing was performed on the probands (N = 133) and consented parents (114 parent-child trios, and 15 parent-child duos) and the GeneVetter analysis tool used to identify damaging coding sequence variants in 163 genes associated with the positive regulation of angiogenesis (PRA) (GO:0045766). RESULTS: In total, 117 damaging variants were identified in PRA genes in 133 congenital heart defect probands with 73 subjects having at least 1 variant. Presence of a damaging PRA variant was associated with increased umbilical artery pulsatility index (mean 1.11 with variant vs 1.00 without; P = .01). The presence of a damaging PRA variant was also associated with lower neonatal length and head circumference for age z score at birth (mean -0.44 and -0.47 with variant vs 0.23 and -0.05 without; P = .01 and .04, respectively). During median 3.1 years (IQR 2.0-4.1 years) of follow-up, deaths occurred in 2 of 60 (3.3%) subjects with no PRA variant and in 9 of 73 (12.3%) subjects with 1 or more PRA variants (P = .06). CONCLUSIONS: Damaging variants in proangiogenic genes may impact placental function and are associated with impaired fetal growth in pregnancies involving a fetus with congenital heart defect.
OBJECTIVE: To determine the impact of damaging genetic variation in proangiogenic pathways on placental function, complications of pregnancy, fetal growth, and clinical outcomes in pregnancies with fetal congenital heart defect. STUDY DESIGN: Families delivering a baby with a congenital heart defect requiring surgical repair in infancy were recruited. The placenta and neonate were weighed and measured. Hemodynamic variables were recorded from a third trimester (36.4 ± 1.7 weeks) fetal echocardiogram. Exome sequencing was performed on the probands (N = 133) and consented parents (114 parent-child trios, and 15 parent-child duos) and the GeneVetter analysis tool used to identify damaging coding sequence variants in 163 genes associated with the positive regulation of angiogenesis (PRA) (GO:0045766). RESULTS: In total, 117 damaging variants were identified in PRA genes in 133 congenital heart defect probands with 73 subjects having at least 1 variant. Presence of a damaging PRA variant was associated with increased umbilical artery pulsatility index (mean 1.11 with variant vs 1.00 without; P = .01). The presence of a damaging PRA variant was also associated with lower neonatal length and head circumference for age z score at birth (mean -0.44 and -0.47 with variant vs 0.23 and -0.05 without; P = .01 and .04, respectively). During median 3.1 years (IQR 2.0-4.1 years) of follow-up, deaths occurred in 2 of 60 (3.3%) subjects with no PRA variant and in 9 of 73 (12.3%) subjects with 1 or more PRA variants (P = .06). CONCLUSIONS: Damaging variants in proangiogenic genes may impact placental function and are associated with impaired fetal growth in pregnancies involving a fetus with congenital heart defect.
Authors: Jill J Savla; Mary E Putt; Jing Huang; Samuel Parry; Julie S Moldenhauer; Samantha Reilly; Olivia Youman; Jack Rychik; Laura Mercer-Rosa; J William Gaynor; Steven M Kawut Journal: J Am Heart Assoc Date: 2022-01-11 Impact factor: 6.106
Authors: Rachel L Leon; Imran N Mir; Christina L Herrera; Kavita Sharma; Catherine Y Spong; Diane M Twickler; Lina F Chalak Journal: Pediatr Res Date: 2021-04-16 Impact factor: 3.953