When a synonymous mutation breaks the silence in a thalassaemia patient

Abstract

SummarySynonymous mutations were considered to lack functional roles in human diseases; however, distinguishing deleterious synonymous mutations from benign ones is still a challenge. In this article, we identified a deleterious synonymous mutation β‐codon 16 (C>T). HBB: c.51C>T, in compound heterozygous form with known β‐thalassaemia mutation patients who clinically presented as non‐transfusion‐dependent thalassaemia (NTDT). A total of 9 families with 11 compound heterozygous index cases were reported. In the heterozygous state, codon 16 (C>T) mutation results in borderline HbA2 (3.18 ± 0.36%) and slightly reduced RBC indices (RBCs: 4.73 ± 0.75 × 106/μL, Hb: 12.26 ± 2.60 g/dL, MCV: 79.48 ± 8.40 fL, MCH: 25.95 ± 4.15 pg). The compound heterozygous patients showed elevated HbA2 (5.98 ± 1.17%) and HbF (12.75 ± 7.51%) and presented clinically as NTDT with a mean Hb of 6.95 ± 1.29 g/dL. Many of them were dependent on few transfusions and had mild splenomegaly. Of the 11 patients, 5 (45.4%) were treated with hydroxyurea. This study highlights the clinical significance of synonymous mutation, when inherited with other β‐thalassaemia mutations leading to the phenotype of NTDT. Thus, the study would help to improve screening protocols for β‐thalassaemia carriers, which will ultimately improve the prevention programme.