Complete 24 Chromosome Analysis
Comprehensive aneuploidy screening is available to offer to patients pursuing preimplantation genetic screening (PGS). Array CGH (aCGH) allows Reprogenetics to screen all chromosomes in 24-36 hours of sample receipt.
aCGH is an advanced genetic test that must be used in conjunction with in vitro fertilization (IVF) as removal of a cell(s) from an oocyte or embryo is required to perform the analysis. Once the cells are removed they are individually identified, loaded into tubes and sent to Reprogenetics for testing.
The microarray is a treated glass slide with the ability to individually screen multiple samples in a 24-36 hour period. Each samples is unique and the result of one sample is not dependent on the cohort.
Once the samples are received by Reprogenetics the DNA contained in the tubes is amplified and hybridized on a slide with fluorescently labeled control DNA. The resulting fluorescent ratios provide clear clinical diagnosis of copy number aberrations. This diagnosis may contribute to the success of the IVF procedure.
This new technology will enable Reprogenetics to improve screening for genetic defects and improve pregnancy outcome for all patients going through IVF by reducing spontaneous abortions and genetically affected conceptions. In the future we anticipate the ability to combine this technology with detection of other microdeletion syndromes. aCGH enables Reprogenetics to perform high throughput aneuploidy screening from a single cell.
Prior to the availability of complete 24-chromosome screening, Fluorescent InSitu Hybridization (FISH) was considered the Gold Standard for aneuploidy screening.
Reprogenetics presently offers four tests using FISH:
- 3 probe panel – X Y 21
- 5 probe panel – X Y 13 18 21
- 9 probe panel – X Y 13 15 16 17 18 21 22
- 12 probe panel – X Y 8 13 14 15 16 17 18 20 21 22
These tests are based on the frequency of trisomies arriving to term (XY, 13,18,21), those that are common in spontaneous pregnancy losses (16,22,15,21) and those that are most commonly found in day 3 embryos (22,16,21,15,17).
In cases where results are ambiguous, Reprogenetics uses a technique called No Result Rescue (NRR) where telomeric probes are used to bind to a different locus and reanalyze the cells. This method allows for the discrimination between probe overlaps or split signals, and considerably reduces the error rate. Turnaround time for diagnosis is six to twelve hours from the time of sample arrival, depending on whether a third round with telomeric probes is needed. Reprogenetics can also accommodate requests for additional analysis of other chromosomes not covered in the standard test.
Reprogenetics’ scientists are responsible for the development of many of the current approaches to preimplantation diagnosis of translocations. Our team has the most extensive experience in the field with over 1000 cycles performed to date. Custom-made probes, involving three or more probes, are used to diagnose translocations and other chromosomal rearrangements. Diagnosis of translocations can be combined with aneuploidy screening, but the obtaining a result for the translocation is the priority. While FISH is still routinely used to diagnosis translocations, Reprogenetics scientific team is utilizing array technology to perform many translocation tests.
Single Gene Disorders and HLA
Reprogenetics offers PGD for any genetic disease with an identified mutation. Preparation for the test is necessary prior to starting a PGD cycle. In certain cases, it may be necessary to test blood and buccal cells from other family members. All tests must be scheduled in advance and coordinated through the Reprogenetics’ Clinical Genetics Services team.
Reprogenetics is approved by the NYSDOH to offer HLA matching. In HLA matching, embryos are screened for HLA-types compatible to those of an ill child from the patient couple. In cases such as lymphoma, where the child needing stem cell transplantation has an illness that is not caused by the inheritance of a defective gene, HLA-typing is the only testing necessary. However, if the illness is caused by a mutation passed from one generation to the next (parent to child), then an additional test can be performed. The only embryos transferred to the mother’s uterus will be those that are HLA compatible and free of the disease-causing mutation(s). Such embryos are expected to produce healthy stem cells with the correct tissue type for transplantation to their brother or sister.
Reprogenetics has a staff of genetic counselors with specific expertise in PGD to serve the needs of its clients. Although Reprogenetics assumes no obligation to advise you as to your legal requirements as to the provision of PGD test, PGD counseling is recommended for every patient undergoing PGD. For patient convenience, the consultations are conducted by telephone and include a discussion about how the test will be performed, what it will indicate and a review of the applicable Reprogenetics data. A letter will be sent to document such consultations. This service can be customized when necessary.
In order to ensure the best results, PGD cases can only be accepted after fixed samples have been evaluated by the Reprogenetics laboratory. If samples received are suboptimal, embryologists from client centers can be provided with supplementary fixation training in one of the facilities free of charge. Within two weeks notice, Reprogenetics can also place a trained embryologist in an IVF laboratory to perform biopsy and fixation. The cost associated with a consultant embryologist is $1500 per biopsy and fixation procedure plus travel expenses. To arrange a Reprogenetics trained embryologists specializing in biopsy services to come to your IVF Center please contact firstname.lastname@example.org.
Products of Conception
Depending on maternal age, miscarriages occur in 10% – 40% of human pregnancies. More than 50% of these losses are due to chromosome abnormalities, therefore analysis of the chromosomes from the products of conception (POC) is indicated. Until now, conventional karyotyping was used to analyze POC specimens, however, this method requires tissue culture and up to 25% of these cultures fail to grow. Chromosomally abnormal samples, such as monosomies and double aneuploidies habitually fail to grow. Tissue culture of POC specimens is also prone to maternal cell contamination which leads to over-reporting of 46,XX (normal female) karyotypes. Analysis of maternal and fetal DNA using quantitative fluorescent polymerase chain reaction (QF-PCR) technology allows detection of maternal cell contamination as well as some forms of polyploidy. Comparative Genomic Hybridization (CGH) and array CGH have overcome many limitations of conventional testing and are considered a significant advance in POC analysis. Reprogenetics is now offering POC analysis by aCGH with QF-PCR, utilizing our vast clinical experience with CGH, array CGH and molecular genetics.
Advantages of Molecular Karyotyping for POC specimens:
- Quick turn around time- Typically 24~72 hours after sample receipt
- No need for tissue culture- 25% more specimens with results compared to conventional testing
- More reliable results- Maternal cell contamination and poor growth not an issue for aCGH with QF-PCR
- Fewer false negative results-more than 60% of specimens definitively diagnosed compared to about 50% with conventional karyotyping
- Expected sex ratio of 50:50 confirmed (following elimination of maternal cell contamination)- this confirms that the test is operating as expected with very reliable results
- 6MB resolution allows detection of micro-deletions and duplications- Not detectable by karyotyping
- Well accepted by genetics experts as an alternative to karyotyping
- Formalin-preserved samples can be analyzed- In most cases if specimen was recently prepared
Reprogenetics will apply any out of pocket cost to the patient of POC testing to a future PGD cycle.
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- Munné S, Alonso ML, Grifo J (1996) case report: unusually high rates of aneuploid embryos in a 28-year old woman with incontinentia pigmenti. Cytogenet. Cell Genet., 72:43-45
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- Munné S, Fischer J, Warner A, Chen S, Zouves C, Cohen J, And referring centers PGD group (2006) Preimplantation Genetic Diagnosis Significantly Reduces Pregnancy Loss in Infertile Couples: A Multi-Center Study. Fertil Steril 85:326-332
- Munné S, Fung J, Cassel MJ, Márquez C, Weier HUG (1998) Preimplantation Genetic Analysis of Translocations: Case-Specific Probes for Interphase Cell Analysis. Human Genet, 102:663-674
- Munné S, Gianaroli L, Tur-Kaspa I, Magli C, Sandalinas M, Grifo J, Cram D, Kahraman S, Verlinsky Y, Simpson JL (2007) Sub-standard application of PGS may interfere with its clinical success. Fertil Steril 88:781-784
- Munné S, Grifo J, Cohen J, Weier HUG (1994) Chromosome abnormalities in Arrested Human Preimplantation Embryos: A Multiple Probe Fluorescence In Situ Hybridization (FISH) Study. Am.J.Hum.Genet. 55,1:150-159.
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- Munné S, Magli C, Bahçe M, Fung J, Legator M, Morrison L, Cohen J, Gianaroli L (1998)Preimplantation diagnosis of the aneuploidies most commonly found in spontaneous abortions and live births: XY, 13, 14, 15, 16, 18, 21, 22. Prenat Diagn. 18:1459-1466
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- Munné S, Sandalinas M, Escudero T, Marquez C, Cohen J (2002) Chromosome mosaicism in cleavage stage human embryos: evidence of a maternal age effect. Reprod Biomed Online 4:223-232
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- Munné S, Sandalinas M, Magli M, Gianaroli L, Cohen J, Warburton D (2004) Increased rate of aneuploid embryos in young women with previous aneuploid conceptions. Prenat Diagn. 24:638-647
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- Munné S, Serena C, Colls P, Garrisi J, Zheng X, Cekleniak N, Lenzi M, Hughes P2, Fischer J, Garrisi M, Tomkin G, Cohen J (2007) Maternal age, morphology, development and chromosome abnormalities in over 6000 cleavage-stage embryos. Reproductive Biomedicine Online 14:628-634
- Munné S, Sultan KM, Weier HUG, Grifo J, Cohen J, Rosenwaks Z (1995) Assessment of numerical abnormalities of X, Y, 18 and 16-chromosomes in preimplantation human embryos prior transfer. Am. J. Obs. Gyn 172:1191-1201
- Munné S, Velilla E, Colls P, Garcia-Bermudez M, Vemuri MC, Steuerwald N, Garrisi J, Cohen J (2005) Self correction of chromosomally abnormal embryos in culture and implications for stem cell production. Fertil Steril, 84:331-335
- Munné S, Weier HUG, Grifo J, Cohen J (1994) Chromosome mosaicism in human embryos. Biol. Reprod. 51:373-379
- Munné S, Weier, U (1996) Simultaneous enumeration of chromosomes 13, 18, 21, X and Y in interphase cells for preimplantation genetic diagnosis of aneuploidy. Cytogenet. Cell. Genet 75:263-270
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- Otani T, Roche M, Mizuikea M, Colls P, Escudero T, Munné S (2006) Preimplantation genetic diagnosis significantly improves the pregnancy outcome of translocation carriers with a history of recurrent miscarriage and unsuccessful pregnancies. Reproductive Biomed Online 13:869-874
- Palermo G, Munné S and Cohen J (1994) The human zygote inherits its mitotic potential from the male gamete. Hum.Reprod. 9:1220-1225.
- Sandalinas M, Márquez M, Munné S (2002) Spectral karyotyping of unfertilized and non-inseminated oocytes. Molec Human Reprod, 8:580-585
- Sandalinas M, Sadowy S, Alikani M, Calderon G, Cohen J, Munné S. (2001)Developmental ability of chromosomally abnormal human embryos to develop to the blastocyst stage. Human Reprod, 16:1954-1958
- Santiago Munné, Muhterem Bahçe, Mireia Sandalinas, Tomás Escudero, Carmen Márquez, Esther Velilla, Pere Colls, Maria Oter, Mina Alikani, Jacques Cohen (2004)Differences in chromosome susceptibility to aneuploidy and survival to first trimester. Reproductive Biomedicine Online 8:81-90
- Silber S, Escudero T, Lenahan K, Sadowy S, Abdelhadi I, Kilani Z, Munné S (2003) Chromosomal abnormalities in embryos derived from TESE. Fertil Steril, 30-38
- Stachecki J, Cohen J, Munné S (2005) Cryopreservation of biopsied cleavage stage biopsied embryos. Reproductive Biomed online 6:711-715
- Stachecki J, Munné S, Cohen J (2004) Spindle organization after cryopreservation of mouse, human, and bovine oocytes. Reprod Biomed Online 8:664-672
- Steuerwald N, Bermudez M, Wells D, Munné S, Cohen J (2007) Maternal age-related differential global expression profiles observed in human oocytes. Reproductive Biomed. Online 14:700-708
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- Verlinsky, Y, Cohen J, Munné S, Gianaroli L, Simpson JL, Ferraretti AP, Kuliev A (2004)Over a decade of preimplantation genetic diagnosis experience – a multicenter report . Fertil Steril 82:292-294
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PGD for Chromosomal Rearrangements
Chromosomal rearrangements such as reciprocal/Robertsonian translocations and pericentric and paracentric inversions are well-recognized forms of genetic abnormality. Preimplantation genetic diagnosis can be used to detect chromosomal rearrangements in embryos with the aim of transferring only normal/balanced ones for the establishment of a healthy pregnancy. A large number of cases has been carried out since the first clinical application of PGD for chromosomal rearrangements. Different studies reporting on the outcome of PGD cases for translocation carriers have demonstrated an increase in the chances of sustaining a pregnancy to full term: 85% of pregnancies on average were lost before PGD, while only 0-25% miscarried after PGD. Furthermore, PGD reduces the time needed for carriers of structural chromosome abnormalities to achieve a sustained pregnancy. Studies have shown that patients undergoing PGD achieve pregnancy in an average of 1.2-1.4 IVF cycles (