Whole exome sequencing and rare variant association study to identify genetic modifiers, KLF1 mutations, and a novel double mutation in Thai patients with hemoglobin E/beta-thalassemia
Issued Date
2023-01-01
Resource Type
ISSN
10245332
eISSN
16078454
Scopus ID
2-s2.0-85150531724
Pubmed ID
36939018
Journal Title
Hematology (United Kingdom)
Volume
28
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Hematology (United Kingdom) Vol.28 No.1 (2023)
Suggested Citation
Hantaweepant C., Suktitipat B., Pithukpakorn M., Chinthammitr Y., Limwongse C., Tansiri N., Sawatnatee S., Takpradit C., Rotchanapanya W., Pongudom S., Charoenprasert K., Paiboonsukwong K., Thamprasert W., Nolwachai N., Rattanasawat W., Sae-Aeng B., Khorwanichakij N., Saetow P., Saengboon S., Kamjornpreecha K., Pholmoo W., Dujjawan B., Siritanaratkul N. Whole exome sequencing and rare variant association study to identify genetic modifiers, KLF1 mutations, and a novel double mutation in Thai patients with hemoglobin E/beta-thalassemia. Hematology (United Kingdom) Vol.28 No.1 (2023). doi:10.1080/16078454.2023.2187155 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/82554
Title
Whole exome sequencing and rare variant association study to identify genetic modifiers, KLF1 mutations, and a novel double mutation in Thai patients with hemoglobin E/beta-thalassemia
Author(s)
Hantaweepant C.
Suktitipat B.
Pithukpakorn M.
Chinthammitr Y.
Limwongse C.
Tansiri N.
Sawatnatee S.
Takpradit C.
Rotchanapanya W.
Pongudom S.
Charoenprasert K.
Paiboonsukwong K.
Thamprasert W.
Nolwachai N.
Rattanasawat W.
Sae-Aeng B.
Khorwanichakij N.
Saetow P.
Saengboon S.
Kamjornpreecha K.
Pholmoo W.
Dujjawan B.
Siritanaratkul N.
Suktitipat B.
Pithukpakorn M.
Chinthammitr Y.
Limwongse C.
Tansiri N.
Sawatnatee S.
Takpradit C.
Rotchanapanya W.
Pongudom S.
Charoenprasert K.
Paiboonsukwong K.
Thamprasert W.
Nolwachai N.
Rattanasawat W.
Sae-Aeng B.
Khorwanichakij N.
Saetow P.
Saengboon S.
Kamjornpreecha K.
Pholmoo W.
Dujjawan B.
Siritanaratkul N.
Author's Affiliation
Siriraj Hospital
Police General Hospital
Lerdsin Hospital
Faculty of Medicine, Thammasat University
Mahidol University
Institute of Molecular Biosciences, Mahidol University
Charoenkrung Pracharak Hospital
Saraburi Hospital
Chaophra Yommarat Hospital
Pathum Thani Hospital
Banphaeo General Hospital
Nakhon Pathom Hospital
Sunpasitthiprasong Hospital
Sisaket Hospital
Udonthani Hospital
Chiangrai Prachanukroh Hospital
Uttaradit Hospital
Police General Hospital
Lerdsin Hospital
Faculty of Medicine, Thammasat University
Mahidol University
Institute of Molecular Biosciences, Mahidol University
Charoenkrung Pracharak Hospital
Saraburi Hospital
Chaophra Yommarat Hospital
Pathum Thani Hospital
Banphaeo General Hospital
Nakhon Pathom Hospital
Sunpasitthiprasong Hospital
Sisaket Hospital
Udonthani Hospital
Chiangrai Prachanukroh Hospital
Uttaradit Hospital
Other Contributor(s)
Abstract
Objectives: Clinical manifestations of patients with Hemoglobin E/beta-thalassemia vary from mild to severe phenotypes despite exhibiting the same genotype. Studies have partially identified genetic modifiers. We aimed to study the association between rare variants in protein-coding regions and clinical severity in Thai patients. Methods: From April to November 2018, a case–control study was conducted based on clinical information and DNA samples collected from Thai patients with hemoglobin E/beta-thalassemia over the age of four years. Cases were patients with severe symptoms, while patients with mild symptoms acted as controls. Whole exome sequencing and rare variant association study were used to analyze the data. Results: All 338 unrelated patients were classified into 165 severe and 173 mild cases. Genotypes comprised 81.4% of hemoglobin E/beta-thalassemia, 2.7% of homozygous or compound heterozygous beta-thalassemia, and 0.3% of (δβ)0 thalassemia Hb E while 15.7% of samples were not classified as beta-thalassemia. A novel cis heterozygotes of IVS I-7 (A > T) and codon 26 (G > A) was identified. Six genes (COL4A3, DLK1, FAM186A, PZP, THPO, and TRIM51) showed the strongest associations with severity (observed p-values of <0.05; significance lost after correction for multiplicity). Among known modifiers, KLF1 variants were found in four mild patients and one severe patient. Conclusion: No rare variants were identified as contributors to the clinical heterogeneity of hemoglobin E/beta-thalassemia. KLF1 mutations are potential genetic modifiers. Studies to identify genetic factors are still important and helpful for predicting severity and developing targeted therapy.