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

Autor: Chattree Hantaweepant, Bhoom Suktitipat, Manop Pithukpakorn, Yingyong Chinthammitr, Chanin Limwongse, Nawaporn Tansiri, Surasak Sawatnatee, Chayamon Takpradit, Wannaphorn Rotchanapanya, Saranya Pongudom, Kanyaporn Charoenprasert, Kittiphong Paiboonsukwong, Wichuda Thamprasert, Narumol Nolwachai, Wanlapa Rattanasawat, Busakorn Sae-Aeng, Nisachon Khorwanichakij, Putchong Saetow, Supawee Saengboon, Krittichat Kamjornpreecha, Wikanda Pholmoo, Boonyanuch Dujjawan, Noppadol Siritanaratkul
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Hematology, Vol 28, Iss 1 (2023)
Druh dokumentu: article
ISSN: 16078454
1607-8454
DOI: 10.1080/16078454.2023.2187155
Popis: ABSTRACTObjectives 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
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