Clinical and haematological characteristics of 38 individuals with Hb G‐Makassar in Malaysia

Abstract

Haemoglobin (Hb) G‐Makassar is a rare Hb variant. It presents a diagnostic challenge as it imitates sickle Hb (Hb S) in standard electrophoresis and high‐performance liquid chromatography assays requiring DNA analysis to confirm diagnosis. Both have point mutations in codon 6, exon 1 in the β‐globin (HBB) gene with different pathogenicities. This study describes the clinical phenotype, haematology and genotype of Hb G‐Makassar. Clinical and laboratory data of 38 cases of Hb G‐Makassar over 8 years were analysed. Hb G‐Makassar was confirmed by a direct sequencing of HBB gene and co‐inheritance of α‐thalassaemia determined through multiplex gap‐PCR and multiplex Amplification Refractory Mutation System polymerase chain reaction. All cases were Malays, predominantly from Terengganu (n = 20, 52.6%). There were 14 (36.8%) males and 24 (63.2%) females with median age of 25 years. Majority (n = 33, 86.8%) had features of thalassaemia trait with mean ± SD for Hb, mean cell volume (MCV) and mean cell haemoglobin (MCH) as 13.21 g/dL ± 1.69, 73.06 ± 4.48 fL and 24.71 ± 1.82 pg, respectively. None had evidence of haemolysis or thromboembolic complications. Six genotypes were identified; ßG‐Makassar/ß,αα/αα (n = 19, 50.0%), ßG‐Makassar/ßE,αα/αα (n = 4, 10.5%), ßG‐Makassar/ßNewYork,αα/αα (n = 1, 2.6%), ßG‐Makassar/ß,αα/‐α (n = 11, 28.9%), ßG‐Makassar/ß,αα/αAdanaα (n = 2, 5.3%) and ßG‐Makassar/ß,αα/–SEA (n = 1, 2.6%). The ßG‐Makassar/ß,αα/αα showed that features of thalassaemia trait with mean ± SD for Hb, MCV and MCH were 13.74 g/dL ± 2.40, 76.18 ± 6.02 fL and 25.79 ± 2.41 pg, respectively. This is the largest study reporting a significant number of Hb G‐Makassar in Malaysia. Although the mutation is similar to Hb S, the phenotype is benign.

Molecular epidemiology and hematological profiles of hemoglobin variants in southern Thailand

“…Thus, molecular testing is essential for differential diagnosis. Furthermore, we reported two cases of Hb G-Makassar with Hb E, presenting mild clinical phenotypes similar to that in a previous report 39 .…”

“…Accordingly, Hb C is predominantly observed in southern Thailand, where malaria is endemic. Moreover, Hb G-Makassar is frequently observed in the southern population, similar to that in the Malaysian population 39 . Hb G-Makassar comigrated at the same retention time as that for Hb S, as determined using the CE technique.…”

Installation of HbG-Makassar by base editing restores hemoglobin function: a transformative therapy for sickle cell disease

“…18,19 Recently, a larger study involving individuals with heterozygous HbG-Makassar/beta thalassemia in Malaysia indicated that the HbG-Makassar behaves as a benign hemoglobin variant. 20 An HbGG individual was reported to have normal red cell indices and was also pregnant at the time of the report. 21 In a more recent study, the conversion of HbS to HbG-Makassar through base editing in a SCD mouse model showed the promising potential of this gene editing approach to correct the pathophysiology associated with sickle cell disease.…”

Characterization of New Alpha Zero (α0) Thalassaemia Deletion (−−GB) among Malays in Malaysian Population

“…The mutation spectrum of thalassaemia is unique, with some diversity and peculiarity according to specific geographical location and distinctive ethnic groups [19,20]. In Malaysia, few alpha and beta variants have been reported as unique among Malays, namely α2 Codon 141 (CGT>CCT) Hb Singapore NG_000006.1:g.34459G>C, [20] and Codon 6 [GAG>GCG] Hb G-Makassar (NG_000007.3:g.70614A>C) [21]. In 2019, Malaysian Thalassaemia Registry reported a total of 8178 registered thalassaemia patients, of which majority of them suffered from HbE/β-thal; followed by β-thal major (β-TM); Hb H disease; β-thal intermedia (β-TI); and others, with the percentage of 35.19%, 32.66%, 19.48%, 9.02%, and 3.64%, respectively [22,23].…”