Research Article
Year 2023,
Volume: 13 Issue: 2, 257 - 262, 10.05.2023
Abstract
Amaç: Yaygın görülen bir tek gen hastalığı olan Alfa talasemi, α-globin zincirinin kusurlu sentezi ile ortaya çıkar. Globin genlerindeki bozukluklara bağlı olarak çok geniş bir klinik spektruma yayılan bu hastalıkta çok sayıda belirlenmemiş taşıyıcı olduğu düşünülmektedir. Klinik semptomu olmayan sessiz taşıyıcılardan, rahim içinde ölüme yol açan şiddetli anemi ile kendini gösteren, çok değişken bulgulara sahip genetik bir hastalıktır. Bu çalışmada bu amaçla alfa globin gen mutasyonu sıklığının ve tiplerinin bulunması ve varyasyon saptanan bireylerdeki fenotipik etkiyi görmek amaçlandı.
Gereç ve Yöntemler: HBA1 ve HBA2 genlerindeki intron bölgelerini çevreleyen tüm kodlama bölgesi sanger dizileme ile tespit edildi. Delesyonlar ve duplikasyonlar multipleks ligasyona bağımlı prob amplifikasyonu (MLPA) ile mutasyonlar tespit edildi.
Bulgular: Bölgemizde en sık rastlanan mutasyon tipi olan -3,7 / (%23,18), 3.7 kb’lık delesyon çalışmamızda da en sık olarak görülürken, diğer mutasyonların dağılımı ise --3,7 (%6,82), -3,7/-- MED (%0,91), --MED (%6,82), --20,5 (3,15), --SEA (%1,36), -4,2 (%0,95), triplikasyon (%0,45) ve nükleotid değişimleri (%4,55) olarak tespit edilmiştir.
Sonuç: Mevcut bilgiler ışığında genotipin fenotipe yansımasının da farklılıklar olması nedeniyle taşıyıcı bireylerin tesbit edilmesi ve genotip fenotip ilişkisinin netleştirilmesi açısından daha geniş popülasyon taramasına ihtiyaç duyulmaktadır. Toplumu alfa talasemi ve ağır klinik seyreden genetik hastalıklar hakkında bilinçlendirmek için taşıyıcı bireylere genetik danışmanlık verilmesi ve genetik çalışmalara ağırlık verilmesi bir gerekliliktir.
References
- Weatherall D, Clegg JB. Inherited haemoglobin disorders: an increasing global health problem. Bulletin of the World Health Organization. 2001; 79(8): 704-712.
- Chui DH, Fucharoen S, Chan V. Hemoglobin H disease: not necessarily a benign disorder. Blood. 2003; 101(3): 791-800.
- Bernards R, Flavell RA. Physical mapping of the globin gene deletion in hereditary persistence of foetal haemoglobin (HPFH). Nucleic Acids Res. 1980; 8(7): 1521-34.
- Higgs DR, Engel JD, Stamatoyannopoulos G. Thalassaemia. Lancet. 2012; 379(9813): 373-83.
- Rosnah B, Rosline H, Zaidah AW, Noor Haslina MN, Marini R, Shafini MY, et al. Detection of common deletional alpha-thalassemia spectrum by molecular technique in kelantan, northeastern malaysia. ISRN Hematol. 2012; 2012: 462969.
- Chui DH, Fucharoen S, Chan V. Hemoglobin H disease: not necessarily a benign disorder. Blood. 2003.
- Lai K, Huang G, Su L, He Y. The prevalence of thalassemia in mainland China: evidence from epidemiological surveys. Sci Rep. 2017; 7(1): 920.
- Tan JA, Lee PC, Wee YC, Tan KL, Mahali NF, George E, et al. High prevalence of alpha- and beta-thalassemia in the Kadazandusuns in East Malaysia: challenges in providing effective health care for an indigenous group. J Biomed Biotechnol. 2010; 2010.
- Azma RZ, Ainoon O, Hafiza A, Azlin I, Noor Farisah AR, Nor Hidayati S, et al. Molecular characteristic of alpha thalassaemia among patients diagnosed in UKM Medical Centre. Malays J Pathol. 2014; 36(1): 27-32.
- Tamary H, Dgany O. (1993). Alpha-Thalassemia. In M. P. Adam, D. B. Everman, G. M. Mirzaa, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. W. Gripp, A. Amemiya (Eds.), GeneReviews((R)). Seattle (WA).
- Kurtoglu AU, Kurtoglu E, Temizkan AK. Effect of iron overload on endocrinopathies in patients with beta-thalassaemia major and intermedia. Endokrynologia Polska. 2012; 63(4): 260-3.
- Casale M, Meloni A, Filosa A, Cuccia L, Caruso V, Palazzi G, et al. Multiparametric Cardiac Magnetic Resonance Survey in Children With Thalassemia Major: A Multicenter Study. Circ Cardiovasc Imaging. 2015; 8(8): e003230.
- Fucharoen S, Winichagoon P. Haemoglobinopathies in southeast Asia. Indian Journal of Medical Research. 2011; 134(4): 498-506.
- Galanello R, Cao A. Gene test review. Alpha-thalassemia. Genet Med. 2011; 13(2): 83-88.
- Kuesap J, Chaijaroenkul W, Rungsihirunrat K, Pongjantharasatien K, Na-Bangchang K. Coexistence of malaria and thalassemia in malaria endemic areas of Thailand. Korean J Parasitol. 2015; 53(3): 265-270.
- Verma IC, Kleanthous M, Saxena R, Fucharoen S, Winichagoon P, Raizuddin S, et al. Multicenter study of the molecular basis of thalassemia intermedia in different ethnic populations. Hemoglobin. 2007; 31(4): 439-452.
- Higgs DR. The molecular basis of alpha-thalassemia. Cold Spring Harb Perspect Med. 2013; 3(1): a011718.
- Farashi S, Harteveld CL. Molecular basis of alpha-thalassemia. Blood Cells Mol Dis. 2018; 70: 43-53.
- Al-Awamy BH. Thalassemia syndromes in Saudi Arabia. Saudi Med J. 2000; 21(1): 8-17.
- Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bulletin of the World Health Organization. 2008; 86(6): 480-7.
- Souza A, Cardoso G, Takanashi S, Guerreiro J. Alpha-thalassemia (3.7 kb deletion) in a population from the Brazilian Amazon region: Santarém, Pará State. Genet Mol Res. 2009; 8(2): 477-81.
- Nadkarni A, Phanasgaonkar S, Colah R, Mohanty D, Ghosh K. Prevalence and molecular characterization of α-thalassemia syndromes among Indians. Genetic testing. 2008; 12(2): 177-80.
- Goh LPW, Chong ETJ, Lee PC. Prevalence of Alpha(alpha)-Thalassemia in Southeast Asia (2010-2020): A Meta-Analysis Involving 83,674 Subjects. Int J Environ Res Public Health. 2020; 17(20).
- Krause MA, Diakite SA, Lopera-Mesa TM, Amaratunga C, Arie T, Traore K, et al. alpha-Thalassemia impairs the cytoadherence of Plasmodium falciparum-infected erythrocytes. PLoS One. 2012; 7(5): e37214.
- Forget BG, Bunn HF. Classification of the disorders of hemoglobin. Cold Spring Harb Perspect Med. 2013; 3(2): a011684.
- Min-Oo G, Gros P. Erythrocyte variants and the nature of their malaria protective effect. Cell Microbiol. 2005; 7(6): 753-63.
- Nosten FH, Phyo AP. New malaria maps. Lancet. 2019; 394(10195): 278-9.
- World malaria report. 2019 Retrieved from https://www.who.int/publications/i/item/9789241565721.
- Harteveld CL, Higgs DR. α-thalassaemia. Orphanet journal of rare diseases. 2010; 5(1): 1-21.
- Berdasco M, Esteller M. Genetic syndromes caused by mutations in epigenetic genes. Hum Genet. 2013; 132(4): 359-83.
- Celik MM, Gunesacar R, Oktay G, Duran GG, Kaya H. Spectrum of alpha-thalassemia mutations including first observation of - -(FIL) deletion in Hatay Province, Turkey. Blood Cells Mol Dis. 2013; 51(1): 27-30.
- Guvenc B, Yildiz SM, Tekinturhan F, Dincer S, Akyuzluer I, Okten S, et al. Molecular characterization of α-thalassemia in Adana, Turkey: a single center study. Acta Haematologica. 2010; 123(4): 197-200.
- Karakaş E, Koç B, Temurhan S, Çilsaat G, Gencay G, Aydın F. (2013, October 2013). Alpha thalassemia mutations in selected cases: Is it possible low cost screen? Paper presented at the 13th International Conference on Thalassemia and Hemoglobinopathies, Abu Dhabi.
- Onay G, Aykut A, Karaca E, al. e. (2013, 2-4 Aralık 2013). Ege bölgesinde alfa talasemi mutasyonlarının dağılımının araştırılması. Paper presented at the Hematolojik Genetik Sempozyumu, İzmir.
- Yavas C, Un C, Celebi E, Gezdirici A, Dogan M, Ili EG, et al. Whole-Exome Sequencing (WES) results of 50 patients with chronic kidney diseases: a perspective of Alport syndrome. Rev Assoc Med Bras (1992). 2022; 68(9): 1282-7.
- Gezdirici A, Gökpınar İli E, Değirmenci B, Aydın Gümüş A, Özdemir G, Erman NA, et al. Hereditary Breast-Ovarian Cancer and BRCA1/BRCA2 Variants: A Single Center Experience. Acta Oncologica Turcica. 2021; 54(3): 264-72.
- Gezdirici A, Terali K, Gulec EY, Bornaun H, Dogan M, Eroz R. An integrated clinical and molecular study of a cohort of Turkish patients with Marfan syndrome harboring known and novel FBN1 variants. J Hum Genet. 2021; 66(7): 647-57.
- Dogan M, Terali K, Eroz R, Demirci H, Kocabay K. Clinical and molecular findings in a Turkish family with an ultra-rare condition, ELP2-related neurodevelopmental disorder. Mol Biol Rep. 2021; 48(1): 701-08.
- Dogan M, Eroz R, Terali K, Gezdirici A, Bolu S. Clinical, radiological and computational studies on two novel GNPTG variants causing mucolipidosis III gamma phenotypes with varying severity. Mol Biol Rep. 2021; 48(2): 1465-74.
- Dogan M, Eroz R, Tecellioglu M, Gezdirici A, Cevik B, Baris I. Clinical and molecular findings in a Turkish family who had a (c.869- 1G>A) splicing variant in PSEN1 gene with a rare condition: the variant alzheimer's disease with spastic paraparesis. Curr Alzheimer Res. 2022; 19(3): 223-35.
- Dogan M, Eroz R, Ozturk E. Chorioretinal dystrophy, hypogonadotropic hypogonadism, and cerebellar ataxia: Boucher-Neuhauser syndrome due to a homozygous (c.3524C>G (p.Ser1175Cys)) variant in PNPLA6 gene. Ophthalmic Genet. 2021; 42(3): 276-82.
- Dogan M, Eroz R, Bolu S, Yuce H, Gezdirici A, Arslanoglu I, et al. Study of ten causal genes in Turkish patients with clinically suspected maturity-onset diabetes of the young (MODY) using a targeted next-generation sequencing panel. Mol Biol Rep. 2022; 49(8): 7483-95.
- Doğan M, Recep E, Hüseyin Y, Özmerdivenli R. Yeni Nesil Dizileme (YND) hakkında bilinenler (literatür taraması). Duzce Medical Journal. 2017; 19(1): 27-30.
Year 2023,
Volume: 13 Issue: 2, 257 - 262, 10.05.2023
Abstract
Aim: Alpha-thalassemia, a common single gene disorder, is caused by defective synthesis of the α-globin chain. It is thought to have a wide clinical spectrum due to defects in globin genes and a large number of indeterminate carriers. It is a genetic disease with highly variable findings ranging from silent carriers with no clinical symptoms to severe anemia leading to in utero death. In this study, we aimed to determine the frequency and types of alpha globin gene mutations and to observe the phenotypic effect in individuals with mutations.
Material and Methods: The coding and intron regions of HBA1 and HBA2 genes were determined by Sanger sequencing. Deletions and duplications were detected by multiplex ligation-dependent probe amplification (MLPA).
Results: This research shows that -3,7 / (%23.18),3.7 kb is the most common mutation type in our deletion research/analysis, and distribution of other mutations is as follows: --3,7 (%6.82), -3,7 / -- MED (%0,91), --MED (%6.82), --20,5 (3.18), --SEA (%1.36), -4,2 (%0.95). This research also demonstrates that triplication is at %0.45 and nucleotide mutation is %4.55. Conclusion: In the light of the available information, since there are differences in the reflection of genotype to phenotype, a larger population screening is needed to identify carrier individuals and to clarify the genotype-phenotype relationship. In order to raise public awareness about alpha thalassemia and genetic diseases with severe clinical course, it is a necessity to provide genetic counseling to carrier individuals and to focus on genetic studies.
References
- Weatherall D, Clegg JB. Inherited haemoglobin disorders: an increasing global health problem. Bulletin of the World Health Organization. 2001; 79(8): 704-712.
- Chui DH, Fucharoen S, Chan V. Hemoglobin H disease: not necessarily a benign disorder. Blood. 2003; 101(3): 791-800.
- Bernards R, Flavell RA. Physical mapping of the globin gene deletion in hereditary persistence of foetal haemoglobin (HPFH). Nucleic Acids Res. 1980; 8(7): 1521-34.
- Higgs DR, Engel JD, Stamatoyannopoulos G. Thalassaemia. Lancet. 2012; 379(9813): 373-83.
- Rosnah B, Rosline H, Zaidah AW, Noor Haslina MN, Marini R, Shafini MY, et al. Detection of common deletional alpha-thalassemia spectrum by molecular technique in kelantan, northeastern malaysia. ISRN Hematol. 2012; 2012: 462969.
- Chui DH, Fucharoen S, Chan V. Hemoglobin H disease: not necessarily a benign disorder. Blood. 2003.
- Lai K, Huang G, Su L, He Y. The prevalence of thalassemia in mainland China: evidence from epidemiological surveys. Sci Rep. 2017; 7(1): 920.
- Tan JA, Lee PC, Wee YC, Tan KL, Mahali NF, George E, et al. High prevalence of alpha- and beta-thalassemia in the Kadazandusuns in East Malaysia: challenges in providing effective health care for an indigenous group. J Biomed Biotechnol. 2010; 2010.
- Azma RZ, Ainoon O, Hafiza A, Azlin I, Noor Farisah AR, Nor Hidayati S, et al. Molecular characteristic of alpha thalassaemia among patients diagnosed in UKM Medical Centre. Malays J Pathol. 2014; 36(1): 27-32.
- Tamary H, Dgany O. (1993). Alpha-Thalassemia. In M. P. Adam, D. B. Everman, G. M. Mirzaa, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. W. Gripp, A. Amemiya (Eds.), GeneReviews((R)). Seattle (WA).
- Kurtoglu AU, Kurtoglu E, Temizkan AK. Effect of iron overload on endocrinopathies in patients with beta-thalassaemia major and intermedia. Endokrynologia Polska. 2012; 63(4): 260-3.
- Casale M, Meloni A, Filosa A, Cuccia L, Caruso V, Palazzi G, et al. Multiparametric Cardiac Magnetic Resonance Survey in Children With Thalassemia Major: A Multicenter Study. Circ Cardiovasc Imaging. 2015; 8(8): e003230.
- Fucharoen S, Winichagoon P. Haemoglobinopathies in southeast Asia. Indian Journal of Medical Research. 2011; 134(4): 498-506.
- Galanello R, Cao A. Gene test review. Alpha-thalassemia. Genet Med. 2011; 13(2): 83-88.
- Kuesap J, Chaijaroenkul W, Rungsihirunrat K, Pongjantharasatien K, Na-Bangchang K. Coexistence of malaria and thalassemia in malaria endemic areas of Thailand. Korean J Parasitol. 2015; 53(3): 265-270.
- Verma IC, Kleanthous M, Saxena R, Fucharoen S, Winichagoon P, Raizuddin S, et al. Multicenter study of the molecular basis of thalassemia intermedia in different ethnic populations. Hemoglobin. 2007; 31(4): 439-452.
- Higgs DR. The molecular basis of alpha-thalassemia. Cold Spring Harb Perspect Med. 2013; 3(1): a011718.
- Farashi S, Harteveld CL. Molecular basis of alpha-thalassemia. Blood Cells Mol Dis. 2018; 70: 43-53.
- Al-Awamy BH. Thalassemia syndromes in Saudi Arabia. Saudi Med J. 2000; 21(1): 8-17.
- Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bulletin of the World Health Organization. 2008; 86(6): 480-7.
- Souza A, Cardoso G, Takanashi S, Guerreiro J. Alpha-thalassemia (3.7 kb deletion) in a population from the Brazilian Amazon region: Santarém, Pará State. Genet Mol Res. 2009; 8(2): 477-81.
- Nadkarni A, Phanasgaonkar S, Colah R, Mohanty D, Ghosh K. Prevalence and molecular characterization of α-thalassemia syndromes among Indians. Genetic testing. 2008; 12(2): 177-80.
- Goh LPW, Chong ETJ, Lee PC. Prevalence of Alpha(alpha)-Thalassemia in Southeast Asia (2010-2020): A Meta-Analysis Involving 83,674 Subjects. Int J Environ Res Public Health. 2020; 17(20).
- Krause MA, Diakite SA, Lopera-Mesa TM, Amaratunga C, Arie T, Traore K, et al. alpha-Thalassemia impairs the cytoadherence of Plasmodium falciparum-infected erythrocytes. PLoS One. 2012; 7(5): e37214.
- Forget BG, Bunn HF. Classification of the disorders of hemoglobin. Cold Spring Harb Perspect Med. 2013; 3(2): a011684.
- Min-Oo G, Gros P. Erythrocyte variants and the nature of their malaria protective effect. Cell Microbiol. 2005; 7(6): 753-63.
- Nosten FH, Phyo AP. New malaria maps. Lancet. 2019; 394(10195): 278-9.
- World malaria report. 2019 Retrieved from https://www.who.int/publications/i/item/9789241565721.
- Harteveld CL, Higgs DR. α-thalassaemia. Orphanet journal of rare diseases. 2010; 5(1): 1-21.
- Berdasco M, Esteller M. Genetic syndromes caused by mutations in epigenetic genes. Hum Genet. 2013; 132(4): 359-83.
- Celik MM, Gunesacar R, Oktay G, Duran GG, Kaya H. Spectrum of alpha-thalassemia mutations including first observation of - -(FIL) deletion in Hatay Province, Turkey. Blood Cells Mol Dis. 2013; 51(1): 27-30.
- Guvenc B, Yildiz SM, Tekinturhan F, Dincer S, Akyuzluer I, Okten S, et al. Molecular characterization of α-thalassemia in Adana, Turkey: a single center study. Acta Haematologica. 2010; 123(4): 197-200.
- Karakaş E, Koç B, Temurhan S, Çilsaat G, Gencay G, Aydın F. (2013, October 2013). Alpha thalassemia mutations in selected cases: Is it possible low cost screen? Paper presented at the 13th International Conference on Thalassemia and Hemoglobinopathies, Abu Dhabi.
- Onay G, Aykut A, Karaca E, al. e. (2013, 2-4 Aralık 2013). Ege bölgesinde alfa talasemi mutasyonlarının dağılımının araştırılması. Paper presented at the Hematolojik Genetik Sempozyumu, İzmir.
- Yavas C, Un C, Celebi E, Gezdirici A, Dogan M, Ili EG, et al. Whole-Exome Sequencing (WES) results of 50 patients with chronic kidney diseases: a perspective of Alport syndrome. Rev Assoc Med Bras (1992). 2022; 68(9): 1282-7.
- Gezdirici A, Gökpınar İli E, Değirmenci B, Aydın Gümüş A, Özdemir G, Erman NA, et al. Hereditary Breast-Ovarian Cancer and BRCA1/BRCA2 Variants: A Single Center Experience. Acta Oncologica Turcica. 2021; 54(3): 264-72.
- Gezdirici A, Terali K, Gulec EY, Bornaun H, Dogan M, Eroz R. An integrated clinical and molecular study of a cohort of Turkish patients with Marfan syndrome harboring known and novel FBN1 variants. J Hum Genet. 2021; 66(7): 647-57.
- Dogan M, Terali K, Eroz R, Demirci H, Kocabay K. Clinical and molecular findings in a Turkish family with an ultra-rare condition, ELP2-related neurodevelopmental disorder. Mol Biol Rep. 2021; 48(1): 701-08.
- Dogan M, Eroz R, Terali K, Gezdirici A, Bolu S. Clinical, radiological and computational studies on two novel GNPTG variants causing mucolipidosis III gamma phenotypes with varying severity. Mol Biol Rep. 2021; 48(2): 1465-74.
- Dogan M, Eroz R, Tecellioglu M, Gezdirici A, Cevik B, Baris I. Clinical and molecular findings in a Turkish family who had a (c.869- 1G>A) splicing variant in PSEN1 gene with a rare condition: the variant alzheimer's disease with spastic paraparesis. Curr Alzheimer Res. 2022; 19(3): 223-35.
- Dogan M, Eroz R, Ozturk E. Chorioretinal dystrophy, hypogonadotropic hypogonadism, and cerebellar ataxia: Boucher-Neuhauser syndrome due to a homozygous (c.3524C>G (p.Ser1175Cys)) variant in PNPLA6 gene. Ophthalmic Genet. 2021; 42(3): 276-82.
- Dogan M, Eroz R, Bolu S, Yuce H, Gezdirici A, Arslanoglu I, et al. Study of ten causal genes in Turkish patients with clinically suspected maturity-onset diabetes of the young (MODY) using a targeted next-generation sequencing panel. Mol Biol Rep. 2022; 49(8): 7483-95.
- Doğan M, Recep E, Hüseyin Y, Özmerdivenli R. Yeni Nesil Dizileme (YND) hakkında bilinenler (literatür taraması). Duzce Medical Journal. 2017; 19(1): 27-30.
There are 43 citations in total.
Details
| Primary Language | Turkish |
|---|---|
| Subjects | Clinical Sciences |
| Journal Section | Research Articles |
| Authors | |
| Publication Date | May 10, 2023 |
| Submission Date | February 4, 2023 |
| Published in Issue | Year 2023 Volume: 13 Issue: 2 |
