Molecular basis and diagnosis of thalassemia

Jee-Soo Lee; Sung Im Cho; Sung Sup Park; Moon-Woo Seong

doi:10.5045/br.2021.2020332

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Blood Res 2021; 56(S1):

Published online April 30, 2021

https://doi.org/10.5045/br.2021.2020332

Molecular basis and diagnosis of thalassemia

Jee-Soo Lee, Sung Im Cho, Sung Sup Park, Moon-Woo Seong

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Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

Correspondence to : Moon-Woo Seong, M.D., Ph.D.
Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
E-mail: mwseong@snu.ac.kr

Received: December 25, 2020; Revised: April 14, 2021; Accepted: April 16, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Abstract

Thalassemia is characterized by the impaired synthesis of globin chains due to disease-causing variants in α- or β-globin genes. In this review, we provide an overview of the molecular basis underlying α- and β-thalassemia, and of the current technologies used to characterize these disease-causing variants for the diagnosis of thalassemia. Understanding these molecular basis and technologies will prove to be beneficial for the accurate diagnosis of thalassemia.

Keywords Thalassemia, α-globin gene, β-globin gene

Article

Review Article

Blood Res 2021; 56(S1): S39-S43

Published online April 30, 2021 https://doi.org/10.5045/br.2021.2020332

Molecular basis and diagnosis of thalassemia

Jee-Soo Lee, Sung Im Cho, Sung Sup Park, Moon-Woo Seong

Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

Correspondence to:Moon-Woo Seong, M.D., Ph.D.
Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
E-mail: mwseong@snu.ac.kr

Received: December 25, 2020; Revised: April 14, 2021; Accepted: April 16, 2021

Abstract

Keywords: Thalassemia, α-globin gene, β-globin gene

Abstract

Fig 1.

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Figure 1.The human α-globin gene cluster on chromosome 16 and the β-globin gene cluster on chromosome 11. The α-globin gene cluster contains three functional globin genes, the embryonic ζ gene (HBZ) and two fetal/adult α, α1 and α2, genes (HBA1 and HBA2) (A). The β-globin gene cluster contains five functional genes, the embryonic ε gene (HBE), two fetal Gγ and Aγ genes (HBG2 and HBG1), and adult δ and β (HBD and HBB) genes (B). HS-40 and the locus control region (LCR) regulate α- and β-globin gene expression, respectively. Hemoglobin differentially expressed at embryonic, fetal, and adult stages are represented (C).

Blood Research 2021; 56: S39-S43https://doi.org/10.5045/br.2021.2020332

Table 1 . Common variants of each variant type of α-thalassemia..

Gene	Variant type	Common variant	Effect
α-globin gene	--/	--^SEA, --^MED, --^FIL	α⁰
	-α/	-α^3.7 and -α^4.2	α⁺
	α^Tα/	α^IVS1(-5nt)α, α^PA(AATAAG)α, α^CSα	α⁺
	αα^T/	HBA1: c.223G>C (Hb^Q-Thailand)	α⁺

Table 2 . Distribution of α-thalassemia genotypes identified in Seoul National University Hospital (South Korea)..

α-thalassemia genotypes	N	%
--^SEA/αα	8	33.3
α^3.7/αα	5	20.8
--^SEA/α^3.7	4	16.7
α^3.7/α^3.7	2	8.3
α^3.7/α212 patchwork	2	8.3
--/αα (ATRA-16 syndrome)	1	4.2
αα/αα (HS-40 deletion)	1	4.2
--^SEA/-α^4.2	1	4.2
Total	24

Table 3 . Types of variants in β-thalassemia..

Gene	Variant type	Effect
β-globin gene	Transcriptional variants	β⁺ or β⁺⁺
	Primary RNA transcript processing	β⁰, β⁺, or β⁺⁺
	3’ UTR or poly-A site	β⁺
	Translation
	Initiation codon	β⁰
	Premature termination codon	β⁰

Abbreviation: UTR, untranslated region..

Table 4 . Molecular spectrum of β-thalassemia identified in Seoul National University Hospital (South Korea)..

HGVS nomenclature	Amino acid change	N of alleles	%
c.-138C>A		1	0.6
c.-81A>G		2	1.2
c.79G>A	p.Glu27Lys	18	11.0
c.92G>A	p.Arg31Lys	1	0.6
c.92+1G>A		2	1.2
c.92+1G>T		2	1.2
c.92+2T>C		1	0.6
c.92+5G>C		3	1.8
c.93-21G>A		3	1.8
c.93-1G>C		2	1.2
c.315+1G>A		12	7.4
c.316-197C>T		1	0.6
c.316-2A>G		1	0.6
c.1A>G	Start loss	2	1.2
c.2T>G	start loss	25	15.3
c.48G>A	p.Trp16*	6	3.7
c.52A>T	p.Lys18*	18	11.0
c.114G>A	p.Trp38*	4	2.5
c.118C>T	p.Gln40*	1	0.6
c.364G>T	p.Glu122*	13	8.0
c.394C>T	p.Gln132*	1	0.6
c.25_26del	p.Lys9Valfs*14	1	0.6
c.27dup	p.Ser10Valfs*14	8	4.9
c.126_129del	p.Phe42Leufs*19	15	9.2
c.201del	p.Val68Cysfs*22	1	0.6
c.217dup	p.Ser72Lysfs*2	2	1.2
c.253_254del	p.Thr85Leufs*6	1	0.6
c.270_271del	p.Ser90Argfs*5	2	1.2
c.287dup	p.Leu97Alafs*6	1	0.6
c.378_379del	p.Val127Alafs*13	1	0.6
c.182T>A	p.Val61Glu	1	0.6
c.383A>G	p.Gln128Arg	2	1.2
HBB whole gene deletion		7	4.3
Beta-globin gene cluster deletion		1	0.6
HBG2-HBB deletion		1	0.6
Total		163

Table 5 . Molecular diagnostic methods for thalassemia..

Mutation type	Method
Deletion	Gap PCR
Deletion	MLPA^a,b)
Non-deletion	Allele-specific PCR
	Reverse dot blotting
	Denaturing gradient gel electrophoresis
	ARMS
	Sanger sequencing^a)
	Next-generation sequencing^a)

^a)Methods currently applied in clinical laboratories in Korea. ^b)Commercial kits available [SALSA MLPA Probemix P140 and P102 (MRC-Holland, Amsterdam, The Netherlands)]..

Abbreviations: ARMS, amplification refractory mutation system; MLPA, multiplex ligation-dependent probe amplification; PCR, polymerase chain reaction..