In this case study, we report an 11-year-old male patient who had jaundice, hepatosplenomegaly, and chronic mild congenital non-autoimmune hemolytic anemia. In our patient, a novel homozygous missense mutation in the PIEZO1 gene was detected using a gene-targeted Next-Generation Sequencing panel: c.3364G>A (p.Glu1122Lys), confirming the diagnosis of DHS.