Arch Iran Med. 2022;25(10): 691-697.
doi: 10.34172/aim.2022.108

Scopus ID: 85146830006
  Abstract View: 187
  PDF Download: 210

Original Article

Genetic Diagnosis of Pyruvate Kinase Deficiency in Undiagnosed Iranian Patients with Severe Hemolytic Anemia, using Whole Exome Sequencing

Jafar Mehrabi Sisakht 1 ORCID logo, Maghsood Mehri 1, Hossein Najmabadi 1,2, Azita Azarkeivan 3, Maryam Neishabury 1* ORCID logo

1 Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
2 Kariminejad-Najmabadi Pathology & Genetics Centre, Tehran, Iran
3 Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
*Corresponding Author: Corresponding Author: Maryam Neishabury, PhD; Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Koodakyar Avenue, Evin, Tehran 1985713834, Iran; Tel: +98-21-22180138; Fax: +98-21-22180138; Email: , Email: nneisha@gmail.com


Background: After ruling out the most common causes of severe hemolytic anemia by routine diagnostic tests, certain patients remain without a diagnosis. The aim of this study was to elucidate the genetic cause of the disease in these patients using next generation sequencing (NGS).

Methods: Four unrelated Iranian families including six blood transfusion dependent cases and their parents were referred to us from a specialist center in Tehran. There was no previous history of anemia in the families and the parents had no abnormal hematological presentations. All probands presented severe congenital hemolytic anemia, neonatal jaundice and splenomegaly. Common causes of hemolytic anemia were ruled out prior to this investigation in these patients and they had no diagnosis. Whole exome sequencing (WES) was performed in the probands and the results were confirmed by Sanger sequencing and subsequent family studies.

Results: We identified five variants in the PKLR gene, including a novel unpublished frameshift in these families. These variants were predicted as pathogenic according to the ACMG guidelines by Intervar and/or Varsome prediction tools. Subsequent family studies by Sanger sequencing supported the diagnosis of pyruvate kinase deficiency (PKD) in six affected individuals and the carrier status of disease in their parents.

Conclusion: These findings show that PKD is among the rare blood disorders that could remain undiagnosed or even ruled out in Iranian population without performing NGS. This could be due to pitfalls in clinical, hematological or biochemical approaches in diagnosing PKD. Furthermore, genotyping PKD patients in Iran could reveal novel mutations in the PKLR gene.

Cite this article as: Mehrabi Sisakht J, Mehri M, Najmabadi H, Azarkeivan A, Neishabury M. Genetic diagnosis of pyruvate kinase deficiency in undiagnosed iranian patients with severe hemolytic anemia, using whole exome sequencing. Arch Iran Med. 2022;25(10):691-697. doi: 10.34172/aim.2022.108
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Submitted: 22 Jul 2021
Revision: 27 Dec 2021
Accepted: 28 Dec 2021
ePublished: 01 Oct 2022
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