Preimplantation genetic haplotyping (PGH) is a clinical method of preimplantation genetic diagnosis (PGD) used to determine the presence of single gene disorders in offspring. PGH provides a more feasible method of gene location than whole-genome association experiments, which are expensive and time-consuming.[1]
PGH differs from common PGD methods such as fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) for two primary reasons. First, rather than focusing on the genetic makeup of an embryo PGH compares the genome of affected and unaffected members of previous generations. This examination of generational variation then allows for a haplotype of genetic markers statistically associated with the target disease to be identified, rather than searching merely for a mutation. PGH is often used to reinforce other methods of genetic testing, and is considered more accurate than certain more common PGD methods because it has been found to reduce risk of misdiagnoses. Studies have found that misdiagnoses due to allele dropout (ADO), one of the most common causes of interpretation error, can be almost eliminated through use of PGH.[2] Further, in the case of mutation due to translocation, PGH is able to detect chromosome abnormality to its full extent by differentiating between embryos carrying balanced forms of a translocation versus those carrying the homologous normal chromosomes.[3] This is an advantage because PGD methods such as FISH are able to reveal whether an embryo will express the phenotypic difference, but not whether an embryo may be a carrier.[4] In 2015, PGH was used in conjunction with a whole-genome amplification (WGA) process to not only diagnose disease but also distinguish meiotic segregation errors from mitotic ones.[5]
Studies are being continually performed in an attempt to utilize and improve PGD methods since their initial invention. It has become increasingly popular because it grants individuals the option of detecting embryo abnormalities before implantation, rather than during the beginning weeks of pregnancy. The latter often results in embryo abortion, presenting an ethical dilemma for many that can now be avoided.
PGH uses information regarding family history in conjunction with the use of linked polymorphic markers such as short tandem repeats (STRs) and single nucleotide polymorphisms (SNPs) to locate genes responsible for disease. Both STRs and SNPs are variations in gene nucleotides, and it is estimated that there are tens of millions of each type of variation in human DNA.[1] High frequency of STRs or SNPs in alleles of affected individuals in comparison to their unaffected direct relatives indicates the origin of a disease causing mutation. They thus "mark" alleles as having a mutation without having to specifically identify the mutation. Because the number of potential STRs and SNPs is so high, a family pedigree helps to narrow the scope of alleles to analyze.[4] Further, understanding how the gene of interest gets expressed over time helps ultimately determine which haplotype is responsible for the alleles linked to the mutation. A haplotype map is thus created, not only exhibiting genes the offspring will contain, but also the parental origin of the genes. Once the alleles that correlate with a mutation are characterized, PGH of the embryos is possible and only embryos carrying the low risk haplotypes are selected for transfer.[2] PGH is performed in vitro until this point, when the chosen embryos get placed in the uterus of a surrogate mother for further development.
Advantagesedit
Once a panel of associated genetic markers has been established for a particular disease it can be used for all carriers of that disease.[6] In contrast, since even a monogenic disease can be caused by many different mutations within the affected gene, conventional PGD methods based on finding a specific mutation would require mutation-specific tests. Thus, PGH widens the availability of PGD to cases where mutation-specific tests are unavailable.
PGH also has an advantage over fluorescence in situ hybridization (FISH) in that FISH is not usually able to make the differentiation between embryos that possess the balanced form of a chromosomal translocation and those carrying the homologous normal chromosomes. This inability can be seriously harmful to the diagnosis made. PGH can make the distinction that FISH often cannot. PGH does this by using polymorphic markers that are better suited at recognizing translocations. These polymorphic markers are able to distinguish between embryos that carried normal, balanced, and unbalanced translocations. FISH also requires more cell fixation for analysis whereas PGH requires only transfer of cells into polymerase chain reaction tubes. The cell transfer is a simpler method and leaves less room for analysis failure.[7]
While PGD was initially carried out to sex rabbits in 1968, human PGD only became available after the development of PCR on a single cell DNA in 1985.[2] PGH was first developed in 2006 at London's Guy's Hospital.[6]
Referencesedit
^ ab"Developing a Haplotype Map of the Human Genome to Find Genes Related to Health and Disease: Meeting Summary". www.genome.gov. Retrieved 2016-03-29.
^ abcCoskun S, Qubbaj W. 2010. Preimplantation genetic diagnosis and selection. J. Reprod Stem Cell Biotechnol 1(1): 120-140.
^Shamash J, Rienstein S, Wolf-Reznik H, Pras E, Dekel M, Litmanovitch T, Brengauz M, Goldman B, Yonath H, Dor J, Levron J, Aviram-Goldring A. Preimplantation genetic haplotyping a new application for diagnosis of translocation carrier’s embryos- preliminary observations of two robertsonian translocation carrier families. J Assist Reprod Genet (2011) 28:77–83.
^ abAltarescu G, Zeevi DA, Zeligson S, Perlberg S, Eldar-Geva T, Margalioth EJ, Levy-Lahad E, Renbaum P. Familial haplotyping and embryo analysis for Preimplantation Genetic Diagnosis (PGD) microarrays: a proof of principle study. J Assist Reprod Genet (2013) 30:1595–1603.
^NewsRx. 2015. Genetics; Studies from Sanger Institute in the Area of Human Genetics Reported (Concurrent Whole-Genome Haplotyping and Copy-Number Profiling of Single Cells). Atlanta (GA): Life Science Weekly.
^ abcRenwick PJ, Trussler J, Ostad-Saffari E, et al. (2006-07-13). "Proof of principle and first cases using preimplantation genetic haplotyping--a paradigm shift for embryo diagnosis". Reprod Biomed Online. 13 (1): 110–9. doi:10.1016/S1472-6483(10)62024-X. PMID 16820122.
^Shamash, J. et al. (2011). Preimplantation genetic haplotyping a new application for diagnosis of translocation carrier’s embryos – preliminary observations of two robertsonian trans-location carrier families. Journal of Assisted Reproduction and Genetics, 28(1), 77-83.
External linksedit
. PGH Press Release. 2006 Guy's and St Thomas' NHS Foundation Trust. 2006-09-12. Archived from the original on 2006-09-30. Retrieved 2006-09-26.
May 08, 2024
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Preimplantation genetic haplotyping PGH is a clinical method of preimplantation genetic diagnosis PGD used to determine the presence of single gene disorders in offspring PGH provides a more feasible method of gene location than whole genome association experiments which are expensive and time consuming 1 PGH differs from common PGD methods such as fluorescence in situ hybridization FISH and polymerase chain reaction PCR for two primary reasons First rather than focusing on the genetic makeup of an embryo PGH compares the genome of affected and unaffected members of previous generations This examination of generational variation then allows for a haplotype of genetic markers statistically associated with the target disease to be identified rather than searching merely for a mutation PGH is often used to reinforce other methods of genetic testing and is considered more accurate than certain more common PGD methods because it has been found to reduce risk of misdiagnoses Studies have found that misdiagnoses due to allele dropout ADO one of the most common causes of interpretation error can be almost eliminated through use of PGH 2 Further in the case of mutation due to translocation PGH is able to detect chromosome abnormality to its full extent by differentiating between embryos carrying balanced forms of a translocation versus those carrying the homologous normal chromosomes 3 This is an advantage because PGD methods such as FISH are able to reveal whether an embryo will express the phenotypic difference but not whether an embryo may be a carrier 4 In 2015 PGH was used in conjunction with a whole genome amplification WGA process to not only diagnose disease but also distinguish meiotic segregation errors from mitotic ones 5 Studies are being continually performed in an attempt to utilize and improve PGD methods since their initial invention It has become increasingly popular because it grants individuals the option of detecting embryo abnormalities before implantation rather than during the beginning weeks of pregnancy The latter often results in embryo abortion presenting an ethical dilemma for many that can now be avoided Contents 1 Procedure 2 Advantages 3 Uses 4 History 5 References 6 External linksProcedure editPGH uses information regarding family history in conjunction with the use of linked polymorphic markers such as short tandem repeats STRs and single nucleotide polymorphisms SNPs to locate genes responsible for disease Both STRs and SNPs are variations in gene nucleotides and it is estimated that there are tens of millions of each type of variation in human DNA 1 High frequency of STRs or SNPs in alleles of affected individuals in comparison to their unaffected direct relatives indicates the origin of a disease causing mutation They thus mark alleles as having a mutation without having to specifically identify the mutation Because the number of potential STRs and SNPs is so high a family pedigree helps to narrow the scope of alleles to analyze 4 Further understanding how the gene of interest gets expressed over time helps ultimately determine which haplotype is responsible for the alleles linked to the mutation A haplotype map is thus created not only exhibiting genes the offspring will contain but also the parental origin of the genes Once the alleles that correlate with a mutation are characterized PGH of the embryos is possible and only embryos carrying the low risk haplotypes are selected for transfer 2 PGH is performed in vitro until this point when the chosen embryos get placed in the uterus of a surrogate mother for further development Advantages editOnce a panel of associated genetic markers has been established for a particular disease it can be used for all carriers of that disease 6 In contrast since even a monogenic disease can be caused by many different mutations within the affected gene conventional PGD methods based on finding a specific mutation would require mutation specific tests Thus PGH widens the availability of PGD to cases where mutation specific tests are unavailable PGH also has an advantage over fluorescence in situ hybridization FISH in that FISH is not usually able to make the differentiation between embryos that possess the balanced form of a chromosomal translocation and those carrying the homologous normal chromosomes This inability can be seriously harmful to the diagnosis made PGH can make the distinction that FISH often cannot PGH does this by using polymorphic markers that are better suited at recognizing translocations These polymorphic markers are able to distinguish between embryos that carried normal balanced and unbalanced translocations FISH also requires more cell fixation for analysis whereas PGH requires only transfer of cells into polymerase chain reaction tubes The cell transfer is a simpler method and leaves less room for analysis failure 7 Uses editPGH has been used to screen for Cystic fibrosis 6 Duchenne muscular dystrophy Huntington s disease Spinal muscular atrophy Alport s syndrome Von Hippel Lindau disease Sickle cell disease Hydatidiform moleHistory editWhile PGD was initially carried out to sex rabbits in 1968 human PGD only became available after the development of PCR on a single cell DNA in 1985 2 PGH was first developed in 2006 at London s Guy s Hospital 6 References edit a b Developing a Haplotype Map of the Human Genome to Find Genes Related to Health and Disease Meeting Summary www genome gov Retrieved 2016 03 29 a b c Coskun S Qubbaj W 2010 Preimplantation genetic diagnosis and selection J Reprod Stem Cell Biotechnol 1 1 120 140 Shamash J Rienstein S Wolf Reznik H Pras E Dekel M Litmanovitch T Brengauz M Goldman B Yonath H Dor J Levron J Aviram Goldring A Preimplantation genetic haplotyping a new application for diagnosis of translocation carrier s embryos preliminary observations of two robertsonian translocation carrier families J Assist Reprod Genet 2011 28 77 83 a b Altarescu G Zeevi DA Zeligson S Perlberg S Eldar Geva T Margalioth EJ Levy Lahad E Renbaum P Familial haplotyping and embryo analysis for Preimplantation Genetic Diagnosis PGD microarrays a proof of principle study J Assist Reprod Genet 2013 30 1595 1603 NewsRx 2015 Genetics Studies from Sanger Institute in the Area of Human Genetics Reported Concurrent Whole Genome Haplotyping and Copy Number Profiling of Single Cells Atlanta GA Life Science Weekly a b c Renwick PJ Trussler J Ostad Saffari E et al 2006 07 13 Proof of principle and first cases using preimplantation genetic haplotyping a paradigm shift for embryo diagnosis Reprod Biomed Online 13 1 110 9 doi 10 1016 S1472 6483 10 62024 X PMID 16820122 Shamash J et al 2011 Preimplantation genetic haplotyping a new application for diagnosis of translocation carrier s embryos preliminary observations of two robertsonian trans location carrier families Journal of Assisted Reproduction and Genetics 28 1 77 83 External links edit Revolutionary new technology will allow more couples to benefit from preimplantation genetic diagnosis PGH Press Release 2006 Guy s and St Thomas NHS Foundation Trust 2006 09 12 Archived from the original on 2006 09 30 Retrieved 2006 09 26 Retrieved from https en wikipedia org w index php title Preimplantation genetic haplotyping amp oldid 1182156906, wikipedia, wiki, book, books, library,
