Supplementary Material for: Congenital Erythropoietic Porphyria in a Neonate: Utility of Rapid Whole Genome Sequencing - A Case Report

Introduction: Congenital erythropoietic porphyria (CEP), especially neonatal-onset CEP, is an ultra-rare autosomal recessive disorder caused by variations in the UROS gene that may mimic severe systemic conditions, which can delay diagnosis. Case Presentation: We report the case of a male neonate born with asphyxia, hepatosplenomegaly, cytopenia, and multiorgan dysfunction, initially suspected to have familial hemophagocytic lymphohistiocytosis. Targeted panels for familial hemophagocytic lymphohistiocytosis and autoinflammatory disorders yielded negative results. Red urine and photosensitive blistering lesions were observed. Rapid trio whole genome sequencing identified a homozygous NM_000375.3 (UROS):c.562G>T (p.Gly188Trp) variant that had previously only been reported in compound heterozygous patients and classified as pathogenic in ClinVar (RCV000003959). Subsequent biochemical testing confirmed markedly elevated porphyrin levels, establishing a diagnosis of CEP. Conclusion: This case highlights the diagnostic challenges of neonatal CEP, where systemic illness may obscure the classical signs. This underscores the value of a genomics-first approach in critically ill neonates.