Prospective cohort study for identification of underlying genetic causes in neonatal encephalopathy using whole-exome sequencing

Purpose: Neonatal encephalopathy, which is characterized by a decreased level of consciousness, occurs in 1-7/1,000 live-term births. In more than half of term newborns, there is no identifiable etiological factor. To identify underlying genetic defects, we applied whole-exome sequencing (WES) in term newborns with neonatal encephalopathy as a prospective cohort study. Methods: Term newborns with neonatal encephalopathy and no history of perinatal asphyxia were included. WES was performed using patient and both parents' DNA. Results: Nineteen patients fulfilling inclusion criteria were enrolled. Five patients were excluded owing to withdrawal of consent, no parental DNA samples, or a genetic diagnosis prior to WES. Fourteen patients underwent WES. We confirmed a genetic diagnosis in five patients (36%): epileptic encephalopathy associated with autosomal dominant de novo variants in SCN2A (p.Met1545Val), KCNQ2 (p.Asp212Tyr), and GNAO1 (p.Gly40Arg); lipoic acid synthetase deficiency due to compound heterozygous variants in LIAS (p.Ala253Pro and p.His236Gln); and encephalopathy associated with an X-linked variant in CUL4B (p.Asn211Ser). Conclusion: WES is helpful at arriving genetic diagnoses in neonatal encephalopathy and/or seizures and brain damage. It will increase our understanding and probably enable us to develop targeted neuroprotective treatment strategies.