A 32-week premature infant presented with respiratory failure, later progressing to pulmonary hypertension (PH), liver failure, lactic acidosis, and encephalopathy. Using exome sequencing, this patient was diagnosed with a rare Polymerase Gamma (POLG)-related mitochondrial DNA (mtDNA) depletion syndrome. This case demonstrates that expanding the differential to uncommon diagnoses is important for complex infants, even in premature neonates whose condition may be explained partially by their gestational age (GA). It also shows that patients with complex neonatal diseases with significant family history may benefit from exome sequencing for diagnosis.