4 - Pilot Study to Assess the Diagnostic Yield of Whole Genome Sequencing in Newborns with Neonatal Encephalopathy (GENE Study)

Publication Number: 1003.4

Anna R. Duncan, Mass General Brigham for Children, Charlestown, MA, United States; Julia Davis, MassGeneral Hospital for Children, Cambridge, MA, United States; Francesca Coyne, brigham and womens, Milton, MA, United States; Tricia See, Brigham and Women's Hospital, Arlington, MA, United States; Jinyun Helen Y(. Chen, MGH, Boston, MA, United States; Tina Steele, Brigham and Won=men's Hospital, North Billerica, MA, United States; Myrene Johnson, Purdue Univeristy, Boston, MA, United States; Deborah Cuddyer, Brigham, Boston, MA, United States; Emily M. Herzberg, Mass General Brigham for Children / Harvard Medical School, Lynnfield, MA, United States; Mohamed El-Dib, Brigham and Women's Hospital / Harvard Medical School, Boston, MA, United States; Nina Gold, MassGeneral Hospital for Children, Boston, MA, United States; David A. Sweetser, Massachusetts General Hospital, Boston, MA, United States; Arindam Bhattacharjee, Brigham and Women's, Boston, MA, United States; Richard B. Parad, Harvard Medical School, Boston, MA, United States

Background: Neonatal encephalopathy (NE) is one of the most common risk factors for neurodevelopmental impairment in neonates, occurring in 1-6/1000 live births. Half of NE is thought secondary to a hypoxic ischemic etiology (HIE). The remaining cases occur in newborns with infections, fetal growth restriction or underlying genetic or metabolic disorders. Recent data demonstrate that sequencing of the whole genome (WGS) generates the highest first pass diagnostic yield in neonates. There are currently no prospective studies evaluating WGS diagnostic yield in NE.

Objective: To prospectively use WGS to determine the diagnostic yield of genetic disorders in neonates presenting with NE in two level 3-4 NICUs, with the long-term goal of understanding which infants with NE would benefit most from WGS.

Design/Methods: Newborns admitted to 2 NICUs were screened for NE from Jan to Oct 2025. Inclusion criteria included 1) mild, moderate or severe NE; 2) GA at birth ≥ 37 weeks; 3) absence of a catastrophic sentinel event; 4) negative blood culture; and 5) fetal exposure to < 40g of maternal magnesium. Parental consent was obtained by a Study PI or Genetics Counselor (GC). WGS was performed on 1-2ml of whole blood by Broad Clinical Labs. Results were reviewed by a multidisciplinary neonatal genetics team and returned to the family by the GC and Study PI. Infants with pathogenic variants were seen by Pediatric Genetics. The project was approved by the institutional IRB.

Results: The GENE Study has enrolled 20 out of 48 planned infants with a majority of infants male (males=14, female=6). NE severity ranged from mild to severe (mild n=8, moderate n=11, severe n=1). Of the 20 infants enrolled, WGS has resulted for 18 with 2 pending. Pathogenic variants were present in 2/18 (11%), variants of unknown significance in 4/18 (22%) and carriers in 1/18 (5.6%); 11/18 (61%) were negative. Pathogenic variants were both identified in infants with mild NE (n=2/8, 25%). WGS led to the identification of pathogenic variants associated with NRXN1 related neurodevelopment disorder and Prader Willi Syndrome. In families electing to include secondary findings (n=17/18), one neonate was diagnosed with a likely pathogenic variant in the childhood cancer causing gene SDHC.

Conclusion(s): Early study data demonstrate the feasibility and potential benefit of WGS in neonates who present with NE. Detection of pathogenic variants, even in those with mild NE, may have important implications for not only clinical outcomes but immediate and long-term care. Additional recruitment and analysis will improve insight into the impact of WGS on clinical practice.