Perinatal hypoxic-ischemic encephalopathy is a rare severe condition in which neonates present with encephalopathy and a clinical history suggestive of prenatal or perinatal hypoxic-ischemic injury. Emerging evidence suggests that genetic conditions are frequently identified in cases of perinatal HIE; however, it is unclear which neonates with this diagnosis warrant genetic testing. This study will offer clinical genome sequencing to neonates with HIE who are undergoing total body cooling (therapeutic hypothermia) and their parents.
Delivery ≥35w0d gestation
Diagnosed with moderate or severe HIE, or HIE with seizures
Undergoing total body cooling / therapeutic hypothermia
Able to provide blood or buccal samples during birth hospitalization
Parents/family not willing to allow participation
Inability to collect sufficient neonatal blood samples (in some circumstances, a buccal swab may be used as backup)
Single group
Genome sequencing
GeneticNeonates enrolled in this study will undergo genome sequencing with parental controls as applicable.
Diagnostic yield
The primary outcome will be the number of cases with a pathogenic or likely-pathogenic variant associated with encephalopathy. This will further be stratified by the presence or absence of a perinatal hypoxic insult or sentinel event.
Genome versus exome sequencing
A secondary outcome will be the incremental improvement in genome sequencing versus simulated exome testing. Diagnostic variants will be classified by their genomic location: exonic, intronic, or deep intronic. The rate of diagnostic findings in genomic locations that would be assayed by exome sequencing will be compared to the overall diagnostic rate (including variants in intronic regions that would not be detected on exome sequencing) to determine the incremental diagnostic benefit of genome sequencing over exome sequencing in this population.
Indeterminate results
A secondary outcome will be the identification rate of non-diagnostic / indeterminate results in genes linked to conditions with an overlapping neuromuscular or neurodevelopmental phenotype.
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