Case report: Identification of a rare homozygous missense variant in the PKLR gene reported for the first time in transfusion-dependent Saudi Patient

Red cell pyruvate kinase deficiency is one of the most common erythrocytic glycolytic pathway defects connected with congenital non-spherocytic anemia. The condition inherited as an autosomal recessive Mendelian trait is caused by mutations in the PKLR gene located on chromosome 1q21. Pyruvate kinase enzyme is crucial in the energy-producing glycolysis pathway that provides red blood cells with the primary source of energy (ATP). We report here a case of a Saudi female patient that was initially diagnosed at a few months old with beta-thalassemia major and was treated with regular blood transfusions and iron overload management. At the time of our sample collection, the patient was recently transferred to King Abdul Aziz University Hospital. Genetic testing was performed to identify the disease-contributing variant of beta-thalassemia using TaqMan genotyping of six common beta-thalassemia variants (negative results). NGS targeted HBB gene sequencing which did not reveal any related variants. MLPA was performed to rule out alpha thalassemia diagnosis. The use of whole genome sequencing revealed a rare missense variant in the PKLR gene c.1015G>A (D339N) in a homozygous state that correlates to her severe phenotype. Documenting this incident will aid medical staff in providing appropriate care to similar cases and highlights the importance of following up with the diagnosis investigation process to minimize misdiagnosis incidences.