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

摘要

Introduction Though an increase in Hb A(2) is one of the most key markers of beta-thal carriers, a few independent cases are reported to show elevated Hb A(2) levels caused by mutations in other genes beyond beta-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 A(2). Globin and KLF1 genes analysis was performed, and further whole-exome sequencing was carried to dissect the genetic causes of those positive samples without beta-thalassemic or KLF1 mutations. Results Of these 1439 individuals with elevated Hb A(2), 1381 had a molecular defect in globin genes, and most were beta-thalassemic mutation; 10 had a molecular defect in KLF1 gene. Finally, among the 38 individuals without beta-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 A(2). According to the previous observations that individuals with a combination of beta-thal mutation and a SUPT5H variant might present moderate beta-thaelassemia, these findings emphasized the importance of comprehensive molecular diagnosis to prevent birth defects of beta-thaelassemia caused by rare mutations from modifier genes.

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