Genetics and IVF Institute

Fairfax, VA, United States

Genetics and IVF Institute

Fairfax, VA, United States
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Handyside A.H.,Gynaecology and Genetics Center | Handyside A.H.,University of Leeds | Harton G.L.,Genetics and IVF Institute | Mariani B.,Genetics and IVF Institute | And 5 more authors.
Journal of Medical Genetics | Year: 2010

The use of genome wide single nucleotide polymorphism (SNP) arrays for high resolution molecular cytogenetic analysis using a combination of quantitative and genotype analysis is well established. This study demonstrates that by Mendelian analysis of the SNP genotypes of the parents and a sibling or other appropriate family member to establish phase, it is possible to identify informative loci for each of the four parental haplotypes across each chromosome and map the inheritance of these haplotypes and the position of any crossovers in the proband. The resulting 'karyomap', unlike a karyotype, identifies the parental and grandparental origin of each chromosome and chromosome segment and is unique for every individual being defined by the independent segregation of parental chromosomes and the pattern of non-recombinant and recombinant chromosomes. Karyomapping, therefore, enables both genome wide linkage based analysis of inheritance and detection of chromosome imbalance where either both haplotypes from one parent are present (trisomy) or neither are present (monosomy/deletion). The study also demonstrates that karyomapping is possible at the single cell level following whole genome amplification and, without any prior patient or disease specific test development, provides a universal linkage based methodology for preimplantation genetic diagnosis readily available worldwide.


Fisch G.S.,New York University | Carpenter N.,Center for Genetic Testing | Howard-Peebles P.N.,Genetics and IVF Institute | Holden J.J.A.,Queen's University | And 3 more authors.
American Journal on Intellectual and Developmental Disabilities | Year: 2012

Few studies exist of developmental trajectories in children with intellectual disability, and none for those with subtelomeric deletions. We compared developmental trajectories of children with Wolf-Hirschhorn syndrome to other genetic disorders. We recruited 106 children diagnosed with fragile X, Williams-Beuren syndrome, or Wolf-Hirschhorn syndrome, assessing their intellectual and adaptive behavior abilities. We retested 61 children 2 years later. We compared Time 1 and Time 2 difference scores related to genetic disorder, age, initial IQ, or adaptive behavior composite. Results show genetic disorder and initial IQ score were significant factors for IQ differences, but only genetic disorder affected adaptive behavior differences. Results suggest different gene-brain-behavior pathways likely exist for these genetic disorders. Different developmental trajectories will influence the type and intensity of intervention implemented by caregivers. © EAAIDD.


Harper J.C.,University College London | Coonen E.,Maastricht University | De Rycke M.,Center for Medical Genetics | Harton G.,Reprogenetics | And 6 more authors.
Human Reproduction | Year: 2010

The 10th report of the European Society of Human Reproduction and Embryology (ESHRE) PGD Consortium is presented, documenting cycles collected for the calendar year 2007 and follow-up of the pregnancies and babies born until October 2008 which resulted from these cycles. Since the beginning of the data collections there has been a steady increase in the number of cycles, pregnancies and babies reported annually. For data collection X, 57 centres participated, reporting on 5887 cycles to oocyte retrieval (OR), along with details of the follow-up on 1516 pregnancies and 1206 babies born. A total of 729 OR were reported for chromosomal abnormalities, 110 OR for sexing for X-linked diseases, 1203 OR for monogenic diseases, 3753 OR for preimplantation genetic screening and 92 OR for social sexing. Data X is compared with the cumulative data for data collections I-IX. © 2010 The Author.


Sapp J.C.,National Human Genome Research Institute | Hull S.C.,Human Genome Research Institutes | Duffer S.,Genetics and IVF Institute | Zornetzer S.,Genetics and IVF Institute | And 3 more authors.
Prenatal Diagnosis | Year: 2010

Objective: This study explores ambivalence toward undergoing amniocentesis among pregnant women with overall positive attitudes. Its novelty lies in the characterization of the type and origins of the ambivalence. Method: Thirty-six women between 35 and 44 years of age were recruited from a US prenatal testing center to participate in structured telephone interviews. Results: Thirty women chose to undergo testing. Attitudes toward undergoing amniocentesis were generally positive, although all participants simultaneously described feeling ambivalent. The women desired the information that amniocentesis could provide yet did not want to place their fetus at risk. Participants cited religious, moral, ethical and intellectual values important in shaping their attitudes toward undergoing amniocentesis. Important referents such as partners, other pregnant women, family members and physicians influenced their decisions. Conclusion: Tensions were evident among the intellectual, moral and spiritual values that contribute to ambivalence toward undergoing amniocentesis. Illuminating and discussing such tensions during the genetic counseling sessions prior to testing may resolve some of this ambivalence and thereby increase the quality of decisions women make. Copyright © 2009 John Wiley & Sons, Ltd.


Harton G.L.,Reprogenetics LLC | Harton G.L.,Genetics and IVF Institute | Magli M.C.,Reproductive Medicine Unit | Lundin K.,Sahlgrenska University Hospital | And 4 more authors.
Human Reproduction | Year: 2011

In 2005, the European Society for Human Reproduction and Embryology (ESHRE) Preimplantation Genetic Diagnosis (PGD) Consortium published a set of Guidelines for Best Practice to give information, support and guidance to potential, existing and fledgling PGD programmes (Thornhill AR, De Die-Smulders CE, Geraedts JP, Harper JC, Harton GL, Lavery SA, Moutou C, Robinson MD, Schmutzler AG, Scriven PN et al. ESHRE PGD Consortium best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS). Hum Reprod 2005;20:3548.). The subsequent years have seen the introduction of a number of new technologies as well as the evolution of current techniques. Additionally, in light of ESHREs recent advice on how practice guidelines should be written and formulated, the Consortium believed it was timely to revise and update the PGD guidelines. Rather than one document that covers all of PGD as in the original publication, these guidelines are separated into four new documents that apply to different aspects of a PGD programme; Organization of a PGD centre, fluorescence in situ hybridization-based testing, amplification-based testing and polar body and embryo biopsy for preimplantation genetic diagnosis/screening (PGD/PGS). Here we have updated the sections that pertain to embryology (including cryopreservation) and biopsy of embryos prior to PGD or PGS. Topics covered in this guideline include uses of embryo biopsy, laboratory issues relating to biopsy, timing of biopsy, biopsy procedure and cryopreserving biopsied embryos. © 2010 The Author.


Harton G.L.,Reprogenetics LLC | Harton G.L.,Genetics and IVF Institute | De Rycke M.,Universitair Ziekenhuis | Fiorentino F.,Genoma Laboratories | And 5 more authors.
Human Reproduction | Year: 2011

In 2005, the European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium published a set of Guidelines for Best Practice PGD to give information, support and guidance to potential, existing and fledgling PGD programmes. The subsequent years have seen the introduction of a number of new technologies as well as the evolution of current techniques. Additionally, in light of recent advice from ESHRE on how practice guidelines should be written and formulated, the Consortium believed it was timely to revise and update the PGD guidelines. Rather than one document that covers all of PGD, as in the original publication, these guidelines are separated into four new documents that apply to different aspects of a PGD programme, i.e. Organization of a PGD centre, fluorescence in situ hybridization-based testing, Amplification-based testing and Polar Body and Embryo Biopsy for PGD/preimplantation genetic screening. Here, we have updated the sections that pertain to amplification-based PGD. Topics covered in this guideline include inclusion/exclusion criteria for amplification-based PGD testing, preclinical validation of tests, amplification-based testing methods, tubing of cells for analysis, set-up of local IVF centre and Transport PGD centres, quality control/quality assurance and diagnostic confirmation of untransferred embryos. © 2010 The Author.


Harper J.,University College London | Coonen E.,Maastricht University | De Rycke M.,Center for Medical Genetics | Fiorentino F.,Molecular Genetics Laboratory | And 9 more authors.
Human Reproduction | Year: 2010

Since 2004, there have been 11 randomized controlled trials (RCTs) mainly for advanced maternal age (AMA), which have shown no benefit of performing preimplantation genetic screening (PGS). Ten of the RCTs have been performed at the cleavage stage and one at the blastocyst stage. It is probable that the high levels of chromosomal mosaicism at cleavage stages, which may Result in the tested cell not being representative of the embryo, and the inability to examine all of the chromosomes using fluorescence in situ hybridization, have contributed to the lack of positive outcome from the RCTs. We suggest that future RCTs should examine alternative biopsy timing (polar body and/or trophectoderm biopsy), and should apply technologies that allow more comprehensive testing to include all chromosomes (microarray-based testing) to determine if PGS shows an improvement in delivery rate. Currently there is no evidence that routine PGS is beneficial for patients with AMA and conclusive data (RCTs) on repeated miscarriage, implantation failure and severe male factor are missing. To evaluate benefits of PGS, an ESHRE trial has recently been started on patients with AMA using polar body biopsy and array-comparative genomic hybridization, which should bring more information on this patient group in the near future.


Fisch G.S.,New York University | Carpenter N.,Center for Genetic Testing | Howard-Peebles P.N.,Genetics and IVF Institute | Holden J.J.A.,Queen's University | And 2 more authors.
American Journal of Medical Genetics, Part A | Year: 2010

The course of cognitive-behavioral development in children with intellectual disabilities produced by genetic disorders has only recently begun to be examined systematically. Unfortunately, these studies are few in number. Previously, we examined cognitive-behavioral development in children with the fragile X(FMR1) mutation and found longitudinal decreases in both IQ and adaptive behavior (DQ) scores in most males and females with the full mutation. In this study, we examine longitudinal changes in IQ andDQ in children with neurofibromatosis type 1 (NF1) and Williams-Beuren Syndrome (WBS) by examining differences in composite IQ and DQ scores between the first test (T1) and retest (T2), and compare their developmental trajectory to children with the FMR1 mutation. Sixty-five children with the FMR1 mutation, or NF1, or WBS, ages 4-16 years, were retested two years after initial testing with the Stanford-Binet 4th Edition (SBFE) and the Vineland Adaptive Behavior Scale (VABS). In addition to significant longitudinal declines in IQ and DQnoted previously in children with the FMR1 mutation, we found significant decreases in IQ in males compared to females in the remainder of our sample. We also observed statistically signifi-cant decreases inDQscores among children the FMR1 mutation, as noted previously, but not among children with NF1 or WBS. Moreover, significant declines were found only among males with the FMR1 mutation. Unlike declines in IQ scores, decreases in DQ were not significantly different between males and females. © 2010 Wiley-Liss, Inc.


Harper J.C.,University College London | Harton G.,Genetics and IVF Institute
Fertility and Sterility | Year: 2010

Background: In preimplantation genetic diagnosis (PGD), polymerase chain reaction has been used to detect monogenic disorders, and in PGD/preimplantation genetic screening (PGS), fluorescence in situ hybridization (FISH) has been used to analyze chromosomes. Ten randomized controlled trials (RCTs) using FISH-based PGS on cleavage-stage embryos and one on blastocyst-stage embryos have shown that PGS does not increase delivery rates. Is the failure of PGS due to a fundamental flaw in the idea, or are the techniques that are being used unable to overcome their own, inherent flaws? Array-based technology allows for analysis of all of the chromosomes. Two types of arrays are being developed for use in PGD; array comparative genomic hybridization (aCGH) and single nucleotide polymorphism-based (SNP) arrays. Each array can determine the number of chromosomes, however, SNP-based arrays can also be used to haplotype the sample. Objective(s): To describe aCGH and SNP array technology and make suggestions for the future use of arrays in PGD and PGS. Conclusion(s): If array-based testing is going to prove useful, three steps need to be taken: [1] Validation of the array platform on appropriate cell and tissue samples to allow for reliable testing, even at the single-cell level; [2] deciding which embryo stage is the best for biopsy: polar body, cleavage, or blastocyst stage; [3] performing RCTs to show improvement in delivery rates. If RCTs are able to show that array-based testing at the optimal stage for embryo biopsy increases delivery rates, this will be a major step forward for assisted reproductive technology patients around the world. Copyright © 2010 American Society for Reproductive Medicine, Published by Elsevier Inc.


Schulman J.D.,Genetics and IVF Institute | Stern H.J.,Genetics and IVF Institute
Clinical Genetics | Year: 2015

Huntington disease (HD) is a late-onset, fatal neurodegenerative disorder caused by a (CAG) triplet repeat expansion in the Huntingtin gene that enlarges during male meiosis. In 1996 in this journal, one of us (J.D.S.) presented a methodology to perform pre-implantation genetic diagnosis in families at-risk for HD without revealing the genetic status of the at-risk parent. Despite the introduction of accurate prenatal and pre-implantation genetic testing which can prevent transmission of the abnormal HD gene in the family permanently, utilization of these options is extremely low. In this article, we examine the decision-making process regarding genetic testing in families with HD and discuss the possible reasons for the low uptake among this group. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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