Pyruvate Kinase Deficiency Diagnosis in Undiagnosed Iranian Patients withSevere Hemolytic Anemia

Background: Some patients remain undiagnosed after routine diagnostic tests rule out the mostcommon causes of severe hemolytic anemia. This study aimed to reveal the genetic cause of thedisease in these patients using next-generation sequencing (NGS).Methods: Four unrelated Iranian families including six blood transfusion-dependent cases andtheir parents were referred to us from a specialist center in Tehran. The families had no previousanemia history or abnormal hematological manifestations. Neonatal jaundice, splenomegaly, andsevere hemolytic anemia were observed in all probands. In these patients, common causes ofhemolytic anemia had been ruled out prior to this investigation. In the probands, whole exomesequencing (WES) was performed and the results were confirmed by Sanger sequencing andsegregation analysis.Result: In these families, we detected five variants in the PKLR gene, including a novelframeshift. These variants were classified as pathogenic based on American College of MedicalGenetics (ACMG) guidelines. Subsequent family studies by Sanger sequencing confirmed thediagnosis of pyruvate kinase deficiency (PKD) in six affected individuals and the carrier status oftheir parents.Conclusion: PKD is defined as a rare but common defect in the glycolytic pathway. It isassociated with congenital non-spherocytic hemolytic anemia, with a variety of clinicalmanifestations and severity, ranging from fetal hydrops to fully compensated anemia. Thisdisease may remain undiagnosed or even ruled out in the Iranian population without performingNGS due to pitfalls encountered in clinical, hematological, or biochemical approaches todiagnosis. Moreover, genotyping PKD patients in Iran could reveal novel PKLR mutations

کلیدواژه ها:

Anemia ، PKLR ، Whole Exome Sequencing