Pyruvate Kinase Deficiency: An Underdiagnosed Cause of Severe Hemolytic Anemia in Iranian Population: Insights From Whole Exome Sequencing of Four Families and Screening of a Population-Specific Database.

Introduction: Pyruvate kinase deficiency (PKD) is a potentially underdiagnosed cause of chronic hemolytic anemia worldwide and remains understudied in certain populations, including Iran. Here, we describe PKD diagnoses in seven Iranian patients from four consanguineous families. Additionally, we present evidence from a population-specific database that supports the widespread prevalence of this disease in the country.

Materials and methods: Whole exome sequencing (WES) was performed on probands presenting with hyperbilirubinemia and severe hemolytic anemia, who were referred to us by specialists after exclusion of hemoglobinopathies, autoimmune hemolytic anemia, and G6PD deficiency, with no definitive diagnosis established. Family studies were conducted using Sanger sequencing. The Iranome database was screened for pathogenic PKLR mutations.

Results: Three distinct PKLR variants were identified in these families: a known pathogenic variant, a novel likely pathogenic variant, and a variant of unknown significance that had previously been reported only once in the compound heterozygous state in two Iranian siblings. Also, a retrospective analysis of the Iranome database revealed that 21 individuals from various Iranian ethnic groups, out of 1200, carried one of six distinct variants classified as pathogenic or likely pathogenic based on the American College of Medical Genetics and Genomics (ACMG) guidelines.

Discussion and conclusion: This study provides new insights into the genetic and ethnic diversity of PKD and its prevalence in Iran. It also highlights critical risk factors for PKD in the Iranian population, including clinical and molecular diagnostic challenges, the prevalence of consanguineous marriages, and low public awareness regarding the risks of genetic disorders.