Severe COVID-19 Unveils Atypical Familial Hemophagocytic Lymphohistiocytosis due to a Novel Homozygous PRF1 Variant

Abstract

We report a novel homozygous PRF1 variant, PRF1 (NM001083116.3):c.343G > A (p.Glu115Lys), identified by whole-exome sequencing (WES) in an 11-year-old girl with atypical familial hemophagocytic lymphohistiocytosis (FHL). The variant, inherited from asymptomatic heterozygous parents, was absent or extremely rare in population databases and was predicted to be deleterious by multiple in silico tools. Born to consanguineous parents, the patient presented with recurrent fever, pancytopenia, and multiorgan failure following SARS-CoV-2 infection, further complicated by Epstein-Barr virus (EBV) and cytomegalovirus (CMV) coinfections. Despite intensive immunosuppressive therapy, she developed seizures, an intracranial hemorrhage, and died at age 11. A striking family history of unexplained febrile deaths in infancy and childhood strongly supported autosomal recessive inheritance. It emphasizes the role of viral triggers, especially COVID-19, in revealing genetic predispositions and underscores the importance of genetic screening in atypical cases.