Pre-implantation Genetic Diagnosis of Thalassemias
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Published:
Mar 31, 2018
Keywords:
embryo selection hemoglobinopathy multiplex fluorescent polymerase chain reaction (PCR) pre-implantation genetic diagnosis (PGD) thalassemias
Main Article Content
Abstract
Beta-Thalassemia major, beta-thalassemia-Hb E disease and Hb Bart’s disease are
severe hereditary anemia which are prevalent in Thailand and neighborhood countries.
Thalassemia syndromes and hemoglobinopathy cost signifiant health and economic burden
and sometimes maternal morbidity and mortality. The present strategy to reduce new cases is
population screening, prenatal genetic diagnosis (PND) and the option for termination of affected
pregnancy (TOP) following thoroughly genetic counselling. The advances of reproductive
technology and molecular genetics facilitate genetic testing of the embryos prior to transfer into
the womb, therefore, embryo selection is possible. Pre-implantation genetic diagnosis (PGD)
consists of sampling techniques from the embryos and molecular genetic analysis techniques.
Polar body biopsy, cleavage stage embryo biopsy or blastocyst biopsy can be used for sampling
DNA material from the embryos. Polymerase chain reaction (PCR) is employed for the analysis
of thalassemia mutations. PGD is an alternative to the traditional PND, providing the couples
at risk of having severe thalassemia babies an opportunity to get pregnant with a healthy one
without the need for TOP. Since 2004, a total of 64 PGD cycles have been performed at the
Department of Obstetrics and Gynaecology, Faculty of Medicine, Chiang Mai University, including
37 alpha-thalassemia, 5 beta-thalassemia and 22 beta-thalassemia-Hb E disease, giving rise
to 24 healthy pregnancies (27 babies).
Article Details
How to Cite
(1)
Piyamongkol, W. Pre-Implantation Genetic Diagnosis of Thalassemias. Thai J Obstet Gynaecol 2018, 26, 2-9.
Section
Special Article
References
1. Tongsong T, Wanapirak C, Sirivatanapa P, Sanguansermsri T, Sirichotiyakul S, Piyamongkol W, et al, Prenatal control of severe thalassaemia: Chiang Mai strategy. Prenat Diagn 2000;20:229-34.
2. Hoffbrand AV, Wonke B. Wonke, Iron chelation therapy. J Intern Med Suppl 1997;740:37-41.
3. Srisupundit K, Piyamongkol W, Tongsong T. Identifiation of fetuses with hemoglobin Bart’s disease using middle
cerebral artery peak systolic velocity. Ultrasound Obstet Gynecol 2009;33:694-7.
4. Edwards RG, Gardner RL. Sexing of live rabbit blastocysts. Nature 1967;214:576-7.
5. Edwards RB, Bavister D, Steptoe PC. Early stages of fertilization in vitro of human oocytes matured in vitro.
Nature 1969;221:632-5.
6. Monk M, Handyside A, Hardy K, Whittingham D. Preimplantation diagnosis of defiiency of hypoxanthine
phosphoribosyl transferase in a mouse model for LeschNyhan syndrome. Lancet 1987;2:423-5.
7. Holding C, Monk M. Diagnosis of beta-thalassaemia by DNA amplifiation in single blastomeres from mouse
preimplantation embryos. Lancet 1989;2:532-5.
8. Hardy K, Martin KL, Leese HJ, Winston RM, Handyside AH, et al. Human preimplantation development in vitro
is not adversely affected by biopsy at the 8-cell stage. Hum Reprod 1990;5:708-14.
9. Handyside AH, Kontogianni EH, Hardy K, Winston RM. Pregnancies from biopsied human preimplantation
embryos sexed by Y-specifi DNA amplifiation. Nature 1990;344:768-70.
10. Handyside AH, Pattinson JK, Penketh RJ, Delhanty JD, Winston RM, Tuddenham EG. Biopsy of human preimplantation embryos and sexing by DNA amplifiation. Lancet 1989;1:347-9.
11. Geraedts J, Handyside A, Harper J, Liebaers I, Sermon K, Staessen C, et al, ESHRE preimplantation genetic
diagnosis (PGD) consortium: data collection II (May 2000). Hum Reprod 2000;15:2673-83.
12. Munné S, Dailey T, Sultan KM, Grifo J, Cohen J. The use of fist polar bodies for preimplantation diagnosis of
aneuploidy. Hum Reprod 1995;10:1014-20.
13. Verlinsky Y, Cieslak J, Ivakhnenko V, Lifchez A, Strom C, Kuliev A. Birth of healthy children after preimplantation
diagnosis of common aneuploidies by polar body florescent in situ hybridization analysis. Preimplantation Genetics Group. Fertil Steril 1996;66:126-9.
14. Malter HE, Cohen J. Partial zona dissection of the human oocyte: a nontraumatic method using micromanipulation to assist zona pellucida penetration. Fertil Steril 1989;51:139-48.
15. Veiga A, Sandalinas M, Benkhalifa M, Boada M, Carrera M, Santaló J, et al. Laser blastocyst biopsy for preimplantation diagnosis in the human. Zygote 1997;5:351-4.
16. Harper JC, Coonen E, Handyside AH, Winston RM, Hopman AH, Delhanty JD. Mosaicism of autosomes
and sex chromosomes in morphologically normal, monospermic preimplantation human embryos. Prenat Diagn 1995;15:41-9.
17. Dokras A, Sargent IL, Ross C, Gardner RL, Barlow DH. Trophectoderm biopsy in human blastocysts. Hum Reprod 1990;5:821-5.
18. Griffin DK, Handyside AH, Harper JC, Wilton LJ, Atkinson G, Soussis I, et al. Clinical experience with preimplantation diagnosis of sex by dual florescent in situ hybridization. J Assist Reprod Genet 1994;11:132-43.
19. Conn CM, Harper JC, Winston RM, Delhanty JD. Infertile couples with Rober tsonian translocations:
preimplantation genetic analysis of embryos reveals chaotic cleavage divisions. Hum Genet 1998;102:117-23.
20. Liu J, Lissens W, Van Broeckhoven C, Löfgren A, Camus M, Liebaers I, et al. Normal pregnancy after
preimplantation DNA diagnosis of a dystrophin gene deletion. Prenat Diagn 1995;15:351-8.
21. Dreesen JC, Geraedts JP, Dumoulin JC, Evers JL, Pieters MH. RS46(DXS548) genotyping of reproductive
cells: approaching preimplantation testing of the fragile-X syndrome. Hum Genet 1995;96:323-9.
22. Gibbons WE, Gitlin SA, Lanzendorf SE, Kaufmann RA, Slotnick RN, Hodgen GD. Preimplantation genetic
diagnosis for Tay-Sachs disease: successful pregnancy after pre-embryo biopsy and gene amplifiation by
polymerase chain reaction. Fertil Steril 1995;63:723-8.
23. Harton GL, Tsipouras P, Sisson ME, Starr KM, Mahoney BS, Fugger EF, et al. Preimplantation genetic testing for
Marfan syndrome. Mol Hum Reprod 1996;2:713-5.
24. Piyamongkol W, Harper JC, Sherlock JK, Doshi A, Serhal PF, Delhanty JD, et al. A successful strategy for
preimplantation genetic diagnosis of myotonic dystrophy using multiplex fluorescent PCR. Prenat Diagn 2001;21:223-32.
25. De Vos A, Sermon K, Van de Velde H, Joris H, Vandervorst M, Lissens W, et al. Pregnancy after preimplantation genetic diagnosis for Charcot-MarieTooth disease type 1A. Mol Hum Reprod 1998;4: 978-84.
26. Asangla Ao, Wells D, Handyside AH, Robert ML Winston, Joy DA. Delhantycorresponding author Preimplantation
genetic diagnosis of inherited cancer: familial adenomatous polyposis coli. J Assist Reprod Genet 1998;15:140-4.
27. Sermon K, Goossens V, Seneca S, Lissens W, De Vos A, Vandervorst M, et al. Preimplantation diagnosis for
Huntington’s disease (HD): clinical application and analysis of the HD expansion in affected embryos. Prenat
Diagn 1998;18:1427-36.
28. McGrath JA, Handyside AH. Preimplantation genetic diagnosis of severe inherited skin diseases. Exp Dermatol 1998;7:65-72.
29. Rechitsky S, Strom C, Verlinsky O, Amet T, Ivakhnenko V, Kukharenko V, et al. Allele dropout in polar bodies and
blastomeres. J Assist Reprod Genet 1998;15:253-7.
30. Dreesen JC, Bras M, de Die-Smulders C, Dumoulin JC, Cobben JM, Evers JL, et al. Preimplantation genetic
diagnosis of spinal muscular atrophy. Mol Hum Reprod 1998;4:881-5.
31. Piyamongkol W, Vutyavanich T, Piyamongkol S, Wells D, Kunaviktikul C, Tongsong T, et al. A successful
strategy for Preimplantation Genetic Diagnosis of betathalassemia and simultaneous detection of Down’s syndrome using multiplex florescent PCR. J Med Assoc Thai 2006;89:918-27.
32. H Van de Velde, Sermon K, De Vos A, Lissens W, Joris H, Vandervorst M, et al. Fluorescent PCR and automated
fragment analysis in preimplantation genetic diagnosis for 21-hydroxylase defiiency in congenital adrenal
hyperplasia. Mol Hum Reprod 1999;5:691-6.
33. Ray PF, Harper JC, Ao A, Taylor DM, Winston RM, Hughes M, et al. Successful preimplantation genetic diagnosis for sex Link Lesch--Nyhan Syndrome using specifi diagnosis. Prenat Diagn 1999;19:1237-41.
34. Ioulianos A, Wells D, Harper JC, Delhanty DA. A successful strategy for preimplantation diagnosis of
medium-chain acyl-CoA dehydrogenase (MCAD) defiiency. Prenat Diagn 2000;20:593-8.
35. Piyamongkol W, Vutyavanich T, Sanguansermsri T. Preimplantation genetic diagnosis of alpha-thalassemiaSEA using novel multiplex florescent PCR. J Assist Reprod Genet 2012;29:95-102.
36. Saiki RK, Walsh PS, Levenson CH, Erlich HA. Genetic analysis of amplifid DNA with immobilized sequencespecifi oligonucleotide probes. Proc Natl Acad Sci U S A 1989;86:6230-4.
37. Hardy, K. and A.H. Handyside, Biopsy of cleavage stage human embryos and diagnosis of single gene defects
by DNA amplifiation. Arch Pathol Lab Med 1992;116:388-92.
38. Kontogianni EH, Griffin DK, Handyside AH. Identifying the sex of human preimplantation embryos in X-linked
disease: amplifiation efficiency of a Y-specifi alphoid repeat from single blastomeres with two lysis protocols.
J Assist Reprod Genet 1996;13:125-32.
39. Findlay I, Ray P, Quirke P, Rutherford A, Lilford R. Allelic drop-out and preferential amplifiation in single cells
and human blastomeres: implications for preimplantation diagnosis of sex and cystic fibrosis. Hum Reprod 1995;10:1609-18.
40. Ray PF, Handyside AH. Increasing the denaturation temperature during the fist cycles of amplifiation reduces allele dropout from single cells for preimplantation genetic diagnosis. Mol Hum Reprod 1996;2:213-8.
41. Findlay I, Urquhart A, Quirke P, Sullivan K, Rutherford AJ, Lilford RJ. Simultaneous DNA ‘fingerprinting’, diagnosis of sex and single-gene defect status from single cells. Hum Reprod 1995;10:1005-13.
42. El-Hashemite N, Delhanty JD. A technique for eliminating allele specifi amplifiation failure during DNA amplification of heterozygous cells for preimplantation diagnosis. Mol Hum Reprod 1997;3:975-8.
43. Kuliev A, Rechitsky S, Verlinsky O, Ivakhnenko V, Evsikov S, Wolf G, et al. Preimplantation diagnosis of thalassemias. J Assist Reprod Genet 1998;15:219-25.
44. Piyamongkol W, Bermúdez MG, Harper JC, Wells D. Detailed investigation of factors inflencing amplifiation
efficiency and allele drop-out in single cell PCR: implications for preimplantation genetic diagnosis. Mol Hum Reprod 2003;9:411-20.
45. Sermon K, Lissens W, Joris H, Seneca S, Desmyttere S, Devroey P, et al. Clinical application of preimplantation
diagnosis for myotonic dystrophy. Prenat Diagn 1997;17:925-32.
46. Handyside AH, Lesko JG, Tarín JJ, Winston RM, Hughes MR. Birth of a normal girl after in vitro fertilization and preimplantation diagnostic testing for cystic firosis. N Engl J Med 1992;327:905-9.
47. Wells D, Sherlock JK. Strategies for preimplantation genetic diagnosis of single gene disorders by DNA amplifiation. Prenat Diagn 1998;18:1389-401.
48. Hattori M, Yoshioka K, Sakaki Y. High-sensitive florescent DNA sequencing and its application for detection and mass-screening of point mutations. Electrophoresis 1992;13:560-5.
2. Hoffbrand AV, Wonke B. Wonke, Iron chelation therapy. J Intern Med Suppl 1997;740:37-41.
3. Srisupundit K, Piyamongkol W, Tongsong T. Identifiation of fetuses with hemoglobin Bart’s disease using middle
cerebral artery peak systolic velocity. Ultrasound Obstet Gynecol 2009;33:694-7.
4. Edwards RG, Gardner RL. Sexing of live rabbit blastocysts. Nature 1967;214:576-7.
5. Edwards RB, Bavister D, Steptoe PC. Early stages of fertilization in vitro of human oocytes matured in vitro.
Nature 1969;221:632-5.
6. Monk M, Handyside A, Hardy K, Whittingham D. Preimplantation diagnosis of defiiency of hypoxanthine
phosphoribosyl transferase in a mouse model for LeschNyhan syndrome. Lancet 1987;2:423-5.
7. Holding C, Monk M. Diagnosis of beta-thalassaemia by DNA amplifiation in single blastomeres from mouse
preimplantation embryos. Lancet 1989;2:532-5.
8. Hardy K, Martin KL, Leese HJ, Winston RM, Handyside AH, et al. Human preimplantation development in vitro
is not adversely affected by biopsy at the 8-cell stage. Hum Reprod 1990;5:708-14.
9. Handyside AH, Kontogianni EH, Hardy K, Winston RM. Pregnancies from biopsied human preimplantation
embryos sexed by Y-specifi DNA amplifiation. Nature 1990;344:768-70.
10. Handyside AH, Pattinson JK, Penketh RJ, Delhanty JD, Winston RM, Tuddenham EG. Biopsy of human preimplantation embryos and sexing by DNA amplifiation. Lancet 1989;1:347-9.
11. Geraedts J, Handyside A, Harper J, Liebaers I, Sermon K, Staessen C, et al, ESHRE preimplantation genetic
diagnosis (PGD) consortium: data collection II (May 2000). Hum Reprod 2000;15:2673-83.
12. Munné S, Dailey T, Sultan KM, Grifo J, Cohen J. The use of fist polar bodies for preimplantation diagnosis of
aneuploidy. Hum Reprod 1995;10:1014-20.
13. Verlinsky Y, Cieslak J, Ivakhnenko V, Lifchez A, Strom C, Kuliev A. Birth of healthy children after preimplantation
diagnosis of common aneuploidies by polar body florescent in situ hybridization analysis. Preimplantation Genetics Group. Fertil Steril 1996;66:126-9.
14. Malter HE, Cohen J. Partial zona dissection of the human oocyte: a nontraumatic method using micromanipulation to assist zona pellucida penetration. Fertil Steril 1989;51:139-48.
15. Veiga A, Sandalinas M, Benkhalifa M, Boada M, Carrera M, Santaló J, et al. Laser blastocyst biopsy for preimplantation diagnosis in the human. Zygote 1997;5:351-4.
16. Harper JC, Coonen E, Handyside AH, Winston RM, Hopman AH, Delhanty JD. Mosaicism of autosomes
and sex chromosomes in morphologically normal, monospermic preimplantation human embryos. Prenat Diagn 1995;15:41-9.
17. Dokras A, Sargent IL, Ross C, Gardner RL, Barlow DH. Trophectoderm biopsy in human blastocysts. Hum Reprod 1990;5:821-5.
18. Griffin DK, Handyside AH, Harper JC, Wilton LJ, Atkinson G, Soussis I, et al. Clinical experience with preimplantation diagnosis of sex by dual florescent in situ hybridization. J Assist Reprod Genet 1994;11:132-43.
19. Conn CM, Harper JC, Winston RM, Delhanty JD. Infertile couples with Rober tsonian translocations:
preimplantation genetic analysis of embryos reveals chaotic cleavage divisions. Hum Genet 1998;102:117-23.
20. Liu J, Lissens W, Van Broeckhoven C, Löfgren A, Camus M, Liebaers I, et al. Normal pregnancy after
preimplantation DNA diagnosis of a dystrophin gene deletion. Prenat Diagn 1995;15:351-8.
21. Dreesen JC, Geraedts JP, Dumoulin JC, Evers JL, Pieters MH. RS46(DXS548) genotyping of reproductive
cells: approaching preimplantation testing of the fragile-X syndrome. Hum Genet 1995;96:323-9.
22. Gibbons WE, Gitlin SA, Lanzendorf SE, Kaufmann RA, Slotnick RN, Hodgen GD. Preimplantation genetic
diagnosis for Tay-Sachs disease: successful pregnancy after pre-embryo biopsy and gene amplifiation by
polymerase chain reaction. Fertil Steril 1995;63:723-8.
23. Harton GL, Tsipouras P, Sisson ME, Starr KM, Mahoney BS, Fugger EF, et al. Preimplantation genetic testing for
Marfan syndrome. Mol Hum Reprod 1996;2:713-5.
24. Piyamongkol W, Harper JC, Sherlock JK, Doshi A, Serhal PF, Delhanty JD, et al. A successful strategy for
preimplantation genetic diagnosis of myotonic dystrophy using multiplex fluorescent PCR. Prenat Diagn 2001;21:223-32.
25. De Vos A, Sermon K, Van de Velde H, Joris H, Vandervorst M, Lissens W, et al. Pregnancy after preimplantation genetic diagnosis for Charcot-MarieTooth disease type 1A. Mol Hum Reprod 1998;4: 978-84.
26. Asangla Ao, Wells D, Handyside AH, Robert ML Winston, Joy DA. Delhantycorresponding author Preimplantation
genetic diagnosis of inherited cancer: familial adenomatous polyposis coli. J Assist Reprod Genet 1998;15:140-4.
27. Sermon K, Goossens V, Seneca S, Lissens W, De Vos A, Vandervorst M, et al. Preimplantation diagnosis for
Huntington’s disease (HD): clinical application and analysis of the HD expansion in affected embryos. Prenat
Diagn 1998;18:1427-36.
28. McGrath JA, Handyside AH. Preimplantation genetic diagnosis of severe inherited skin diseases. Exp Dermatol 1998;7:65-72.
29. Rechitsky S, Strom C, Verlinsky O, Amet T, Ivakhnenko V, Kukharenko V, et al. Allele dropout in polar bodies and
blastomeres. J Assist Reprod Genet 1998;15:253-7.
30. Dreesen JC, Bras M, de Die-Smulders C, Dumoulin JC, Cobben JM, Evers JL, et al. Preimplantation genetic
diagnosis of spinal muscular atrophy. Mol Hum Reprod 1998;4:881-5.
31. Piyamongkol W, Vutyavanich T, Piyamongkol S, Wells D, Kunaviktikul C, Tongsong T, et al. A successful
strategy for Preimplantation Genetic Diagnosis of betathalassemia and simultaneous detection of Down’s syndrome using multiplex florescent PCR. J Med Assoc Thai 2006;89:918-27.
32. H Van de Velde, Sermon K, De Vos A, Lissens W, Joris H, Vandervorst M, et al. Fluorescent PCR and automated
fragment analysis in preimplantation genetic diagnosis for 21-hydroxylase defiiency in congenital adrenal
hyperplasia. Mol Hum Reprod 1999;5:691-6.
33. Ray PF, Harper JC, Ao A, Taylor DM, Winston RM, Hughes M, et al. Successful preimplantation genetic diagnosis for sex Link Lesch--Nyhan Syndrome using specifi diagnosis. Prenat Diagn 1999;19:1237-41.
34. Ioulianos A, Wells D, Harper JC, Delhanty DA. A successful strategy for preimplantation diagnosis of
medium-chain acyl-CoA dehydrogenase (MCAD) defiiency. Prenat Diagn 2000;20:593-8.
35. Piyamongkol W, Vutyavanich T, Sanguansermsri T. Preimplantation genetic diagnosis of alpha-thalassemiaSEA using novel multiplex florescent PCR. J Assist Reprod Genet 2012;29:95-102.
36. Saiki RK, Walsh PS, Levenson CH, Erlich HA. Genetic analysis of amplifid DNA with immobilized sequencespecifi oligonucleotide probes. Proc Natl Acad Sci U S A 1989;86:6230-4.
37. Hardy, K. and A.H. Handyside, Biopsy of cleavage stage human embryos and diagnosis of single gene defects
by DNA amplifiation. Arch Pathol Lab Med 1992;116:388-92.
38. Kontogianni EH, Griffin DK, Handyside AH. Identifying the sex of human preimplantation embryos in X-linked
disease: amplifiation efficiency of a Y-specifi alphoid repeat from single blastomeres with two lysis protocols.
J Assist Reprod Genet 1996;13:125-32.
39. Findlay I, Ray P, Quirke P, Rutherford A, Lilford R. Allelic drop-out and preferential amplifiation in single cells
and human blastomeres: implications for preimplantation diagnosis of sex and cystic fibrosis. Hum Reprod 1995;10:1609-18.
40. Ray PF, Handyside AH. Increasing the denaturation temperature during the fist cycles of amplifiation reduces allele dropout from single cells for preimplantation genetic diagnosis. Mol Hum Reprod 1996;2:213-8.
41. Findlay I, Urquhart A, Quirke P, Sullivan K, Rutherford AJ, Lilford RJ. Simultaneous DNA ‘fingerprinting’, diagnosis of sex and single-gene defect status from single cells. Hum Reprod 1995;10:1005-13.
42. El-Hashemite N, Delhanty JD. A technique for eliminating allele specifi amplifiation failure during DNA amplification of heterozygous cells for preimplantation diagnosis. Mol Hum Reprod 1997;3:975-8.
43. Kuliev A, Rechitsky S, Verlinsky O, Ivakhnenko V, Evsikov S, Wolf G, et al. Preimplantation diagnosis of thalassemias. J Assist Reprod Genet 1998;15:219-25.
44. Piyamongkol W, Bermúdez MG, Harper JC, Wells D. Detailed investigation of factors inflencing amplifiation
efficiency and allele drop-out in single cell PCR: implications for preimplantation genetic diagnosis. Mol Hum Reprod 2003;9:411-20.
45. Sermon K, Lissens W, Joris H, Seneca S, Desmyttere S, Devroey P, et al. Clinical application of preimplantation
diagnosis for myotonic dystrophy. Prenat Diagn 1997;17:925-32.
46. Handyside AH, Lesko JG, Tarín JJ, Winston RM, Hughes MR. Birth of a normal girl after in vitro fertilization and preimplantation diagnostic testing for cystic firosis. N Engl J Med 1992;327:905-9.
47. Wells D, Sherlock JK. Strategies for preimplantation genetic diagnosis of single gene disorders by DNA amplifiation. Prenat Diagn 1998;18:1389-401.
48. Hattori M, Yoshioka K, Sakaki Y. High-sensitive florescent DNA sequencing and its application for detection and mass-screening of point mutations. Electrophoresis 1992;13:560-5.