Grace E VanNoy1,2,3, Jill A Madden1,3, Pankaj B Agrawal4,5,6,7, Timothy W Yu8,9,10,11, Cynthia S Gubbels1,12,2,3, Deborah Copenheaver13, Sandra Yang13, Monica H Wojcik1,12,2,3,14, Nina B Gold1,12,15, Casie A Genetti1,3, Joan Stoler1,12, Richard B Parad12,16, Sergei Roumiantsev12,17, Olaf Bodamer1,12,2, Alan H Beggs1,12,3, Jane Juusola13. 1. Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA. 2. Broad Institute of MIT and Harvard, Cambridge, MA, USA. 3. The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA. 4. Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA. pankaj.agrawal@childrens.harvard.edu. 5. Harvard Medical School, Boston, MA, USA. pankaj.agrawal@childrens.harvard.edu. 6. The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA. pankaj.agrawal@childrens.harvard.edu. 7. Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA. pankaj.agrawal@childrens.harvard.edu. 8. Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA. timothy.yu@childrens.harvard.edu. 9. Harvard Medical School, Boston, MA, USA. timothy.yu@childrens.harvard.edu. 10. Broad Institute of MIT and Harvard, Cambridge, MA, USA. timothy.yu@childrens.harvard.edu. 11. The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA. timothy.yu@childrens.harvard.edu. 12. Harvard Medical School, Boston, MA, USA. 13. GeneDx, Inc, Gaithersburg, MD, USA. 14. Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA. 15. Division of Medical Genetics and Metabolism, Massachusetts General Hospital for Children, Boston, MA, USA. 16. Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, MA, USA. 17. Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA.
Abstract
PURPOSE: To investigate the impact of rapid-turnaround exome sequencing in critically ill neonates using phenotype-based subject selection criteria. METHODS: Intensive care unit babies aged <6 months with hypotonia, seizures, a complex metabolic phenotype, and/or multiple congenital malformations were prospectively enrolled for rapid (<7 day) trio-based exome sequencing. Genomic variants relevant to the presenting phenotype were returned to the medical team. RESULTS: A genetic diagnosis was attained in 29 of 50 (58%) sequenced cases. Twenty-seven (54%) patients received a molecular diagnosis involving known disease genes; two additional cases (4%) were solved with pathogenic variants found in novel disease genes. In 24 of the solved cases, diagnosis had impact on patient management and/or family members. Management changes included shift to palliative care, medication changes, involvement of additional specialties, and the consideration of new experimental therapies. CONCLUSION: Phenotype-based patient selection is effective at identifying critically ill neonates with a high likelihood of receiving a molecular diagnosis via rapid-turnaround exome sequencing, leading to faster and more accurate diagnoses, reducing unnecessary testing and procedures, and informing medical care.
PURPOSE: To investigate the impact of rapid-turnaround exome sequencing in critically ill neonates using phenotype-based subject selection criteria. METHODS: Intensive care unit babies aged <6 months with hypotonia, seizures, a complex metabolic phenotype, and/or multiple congenital malformations were prospectively enrolled for rapid (<7 day) trio-based exome sequencing. Genomic variants relevant to the presenting phenotype were returned to the medical team. RESULTS: A genetic diagnosis was attained in 29 of 50 (58%) sequenced cases. Twenty-seven (54%) patients received a molecular diagnosis involving known disease genes; two additional cases (4%) were solved with pathogenic variants found in novel disease genes. In 24 of the solved cases, diagnosis had impact on patient management and/or family members. Management changes included shift to palliative care, medication changes, involvement of additional specialties, and the consideration of new experimental therapies. CONCLUSION: Phenotype-based patient selection is effective at identifying critically ill neonates with a high likelihood of receiving a molecular diagnosis via rapid-turnaround exome sequencing, leading to faster and more accurate diagnoses, reducing unnecessary testing and procedures, and informing medical care.
Entities:
Keywords:
exome sequencing; intensive care unit; neonates
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