Distribution of Alpha Thalassaemia Gene Variants in Diverse Ethnic Populations in Malaysia: Data from the Institute for Medical Research

Abstract

Alpha thalassaemia is highly prevalent in the plural society of Malaysia and is a public health problem. Haematological and molecular data from 5016 unrelated patients referred from various hospitals to the Institute for Medical Research for α thalassaemia screening from 2007 to 2010 were retrieved. The aims of this retrospective analysis were to describe the distribution of various alpha thalassaemia alleles in different ethnic groups, along with their genotypic interactions, and to illustrate the haematological changes associated with each phenotype. Amongst the patients, 51.2% (n = 2567) were diagnosed with α thalassaemia. Of the 13 α thalassaemia determinants screened, eight different deletions and mutations were demonstrated: three double gene deletions, – – SEA, – – THAI, ––FIL; two single-gene deletions, α–3.7 and – α4.2; and three non-deletion mutations, Cd59G > A (haemoglobin [Hb] Adana), Cd125T > C (Hb Quong Sze) and Cd142 (Hb Constant Spring). A high incidence of α–3.7 deletion was observed in Malays, Indians, Sabahans, Sarawakians and Orang Asli people. However, the – – SEA deletion was the most common cause of alpha thalassaemia in Chinese, followed by the α–3.7 deletion. As many as 27 genotypic interactions showed 1023 α thalassaemia silent carriers, 196 homozygous α+ thalassaemia traits, 973 heterozygous α0 thalassaemia carriers and 375 patients with Hb H disease. Statistical analysis showed a significant difference in the distribution of α thalassaemia determinants amongst the various ethnic groups. Hence, the heterogeneous distribution of common determinants indicated that the introduction of an ethnicity-targeted hierarchical α thalassaemia screening approach in this multi-ethnic Malaysian population would be effective.

A Novel Single Gene Deletion (−αMAL3.5) Giving Rise to Silent α Thalassemia Carrier Removing the Entire HBA2 Gene Observed in Two Chinese Patients with Hb H Disease: Case Report of Two Probands

“…6,7 a-thalassemia has a high prevalence in Malaysia and the alleles that make up the various syndromes in the order of their population frequencies are -a 3.7 , --SEA , a CS a, a QZ a, -a 4.2 , --FIL and --THAI . 4 A distinctive prominence in the allelic distribution has been established amongst the three major ethnic groups (Malays, Chinese, and Indians) that constitutes Malaysian population. 4 The deletions -a 3.7 and --SEA are two major alleles with an incidence of 11.6% and 13.3% respectively.…”

“…a-thalassemia trait has three molecular basis -heterozygous a + -thalassemia (silent) carrier (-a/aa or a T a/aa) (with either a deletion or a dysfunctional mutation at one a globin gene; heterozygous a 0 thalassemia (--/aa) where two genes on a single haploid chromosome are deleted; and homozygous a + thalassemia (-a/-a) in which one gene on each haplotype is affected. The carrier is asymptomatic with normal to mild hematological change in red cell indices, 4 while the latter two may show mild to moderate microcytic hypochromic anemia during an incidental routine blood count and their HbA 2 may be normal or slightly depressed. [4][5][6] a-thalassemia intermedia or Hb H disease results from inheritance of just one functional a-globin gene (--/-a).…”

“…The carrier is asymptomatic with normal to mild hematological change in red cell indices, 4 while the latter two may show mild to moderate microcytic hypochromic anemia during an incidental routine blood count and their HbA 2 may be normal or slightly depressed. [4][5][6] a-thalassemia intermedia or Hb H disease results from inheritance of just one functional a-globin gene (--/-a). Clinical presentation of Hb H due to non-deletional types is more severe than the deletional forms.…”

“…3 Though a-thalassemia commonly results from a globin gene deletions, non-deletional forms of a-thalassemia resulting from point mutations in either the a2 (a T a) or a1 (aa T ) gene are not uncommon in Southeast Asia. 4 Deletion or mutation in the duplicated a globin gene pair can result in three clinical phenotypes such as a thalassemia trait, Hb H disease and Hb Bart's hydrops fetalis. a-thalassemia trait has three molecular basis -heterozygous a + -thalassemia (silent) carrier (-a/aa or a T a/aa) (with either a deletion or a dysfunctional mutation at one a globin gene; heterozygous a 0 thalassemia (--/aa) where two genes on a single haploid chromosome are deleted; and homozygous a + thalassemia (-a/-a) in which one gene on each haplotype is affected.…”

“…Clinical presentation of Hb H due to non-deletional types is more severe than the deletional forms. 4 On the severe spectrum of the syndrome, Hb Bart hydrops fetalis, also known as a-thalassemia major (--/--), has no functional a globin gene and thus is incompatible with extra-uterine life. 6,7 a-thalassemia has a high prevalence in Malaysia and the alleles that make up the various syndromes in the order of their population frequencies are -a 3.7 , --SEA , a CS a, a QZ a, -a 4.2 , --FIL and --THAI .…”