A stepwise haematological screening and whole‐exome sequencing reveal multiple mutations from SUPT5H causing an elevation of Hb A₂ from a cohort of 47336 individuals

Abstract

Introduction Though an increase in Hb A2 is one of the most key markers of β‐thal carriers, a few independent cases are reported to show elevated Hb A2 levels caused by mutations in other genes beyond β‐globin gene. Methods We reviewed the haematological indices of 47336 individuals to analyse the phenotype–genotype correlation and identified 1439 individuals (3.04%) positive in the elevation of Hb A2. Globin and KLF1 genes analysis was performed, and further whole‐exome sequencing was carried to dissect the genetic causes of those positive samples without β‐thalassemic or KLF1 mutations. Results Of these 1439 individuals with elevated Hb A2, 1381 had a molecular defect in globin genes, and most were β‐thalassemic mutation; 10 had a molecular defect in KLF1 gene. Finally, among the 38 individuals without β‐thalassemic or KLF1 mutations, 7 were identified to carried a loss‐of‐function mutation in SUPT5H. Conclusion This study has provided a mutation spectrum of SUPT5H in a cohort screening leading to the elevation of Hb A2. According to the previous observations that individuals with a combination of β‐thal mutation and a SUPT5H variant might present moderate β‐thaelassemia, these findings emphasized the importance of comprehensive molecular diagnosis to prevent birth defects of β‐thaelassemia caused by rare mutations from modifier genes.

RNA polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation

“…Taken together, the SUPT5H loss-of-function patient mutations result in a β-thalassemia trait-like phenotype unlinked to HBB. While we were conducting these studies, independent pedigrees with similar phenotypes were reported, lending further support to our genetic findings (Charnay et al 2022;Achour et al 2020;Lou et al 2022). Notably, patients harboring these mutations are relatively healthy, exhibiting subtle but consistent phenotypes: essentially no anemia, but clear signs of β/α-globin chain imbalance.…”