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

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. 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. 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. 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.