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Handyside A.H.,Gynaecology and Genetics Center | Handyside A.H.,University of Leeds
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2012

Chromosome aneuploidy is a major cause of pregnancy loss, abnormal pregnancy and live births following both natural conception and in vitro fertilisation (IVF) and increases exponentially with maternal age in the decade preceding the menopause. Molecular genetic analysis has shown that these are predominantly maternal in origin and trisomies most frequently occur through errors in the first meiotic division. Analysis of chromosome copy number in the three products of female meiosis, the first and second polar bodies and the corresponding zygote by microarray comparative genomic hybridisation (array CGH), in women of advanced maternal age undergoing IVF, has recently revealed a pattern of frequent multiple meiotic errors, caused by premature predivision of sister chromatids in meiosis I and a high incidence of errors in meiosis II. This pattern is similar to those observed in various mouse models which implicate the gradual depletion of cohesins, which are essential for cohesion of sister chromatids, as the primary cause of age related aneuploidy in female meiosis. However, defects in other aspects of meiosis including the formation and stabilisation of chiasmata and the spindle assembly checkpoint (SAC) may also contribute. The challenge remains to explain the molecular basis of 'physiological' rather than 'chronological' female ageing and the contribution of multifactorial causes from the fetal to adult ovary. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure. © 2012 Elsevier B.V.

Handyside A.H.,Gynaecology and Genetics Center | Handyside A.H.,University of Leeds
Obstetrics, Gynaecology and Reproductive Medicine | Year: 2011

Preimplantation genetic diagnosis (PGD) of inherited conditions following in vitro fertilization (IVF) is now clinically well established worldwide and 7000 children have been born. The range of applications includes single gene defects, chromosome aneuploidy and structural abnormalities, and HLA matching, to identify histocompatible embryos for cord blood stem cell transplantation and treatment of existing children affected mainly by blood related conditions. Recently, the use of advanced technologies for genome-wide analysis, such as microarrays, has provided a universal approach for the diagnosis of both inherited genetic defects and chromosomal abnormalities affecting the viability of the embryo. Clinical pregnancy rates have steadily increased with improvements both in the accuracy of the diagnosis and in IVF. Clinical outcomes are similar to those in assisted conception generally, with an increase in prematurity mainly associated with multiple births and no significant increase in congenital abnormalities. Follow up of children born is ongoing but initial studies have been reassuring. © 2010.

Handyside A.H.,Gynaecology and Genetics Center | Handyside A.H.,University of Leeds
Reproductive BioMedicine Online | Year: 2011

Bisignano et al. (2011) argue that, for preimplantation genetic diagnosis (PGD) of aneuploidy for all 24 chromosomes, microarray-based comparative genomic hybridization (array CGH) is superior to the use of single-nucleotide polymorphism (SNP) genotyping arrays. Published studies indicate that both technologies accurately detect aneuploidy of whole chromosomes or chromosome segments. However, given the extra theoretical resolution and parent-of-origin information provided by SNP-based approaches, these may be particularly suited to certain applications such as PGD of single-gene defects or translocation chromosome imbalance combined with comprehensive detection of aneuploidy. A consensus on how to validate aneuploidy testing and all other clinically relevant information resulting from genome-wide analysis is needed urgently. © 2011 Elsevier Inc. All rights reserved.

Magli M.C.,S.I.S.Me.R | Montag M.,University of Bonn | Kster M.,University of Bonn | Muzi L.,S.I.S.Me.R | And 11 more authors.
Human Reproduction | Year: 2011

Background The purpose of this study was to assess the technical aspects related to polar body (PB) biopsy, which might have an influence on the results of the microarray comparative genomic hybridization analysis. Furthermore, a comparison was made between two biopsy methods (mechanical and laser). Methods Biopsy of the first and second PB (PB1 and PB2) was performed by mechanical-or laser-assisted biopsy in two different IVF centres. PBs were separately amplified by whole genome amplification. Results The method of biopsy, mechanical or laser had no influence on the proportion of successfully biopsied oocytes. Especially, for the PB2, the timing of biopsy after ICSI was directly correlated to amplification efficiency. Conclusions Special care has to be taken with respect to the timing of biopsy of the PB2. Mechanical-and laser-assisted biopsy give the same performance in terms of diagnostic efficiency. © 2011 The Author.

Harper J.C.,University College London | Sengupta S.,University College London | Vesela K.,Center for Reproductive Medicine and Preimplantation Diagnosis | Thornhill A.,Gynaecology and Genetics Center | And 4 more authors.
Human Reproduction | Year: 2010

Accreditation according to an internationally recognized standard is increasingly acknowledged as the single most effective route to comprehensive laboratory quality assurance, and many countries are progressively moving towards compulsory accreditation of medical testing laboratories. The ESHRE PGD Consortium and some regulatory bodies recommend that all PGD laboratories should be accredited or working actively towards accreditation, according to the internationally recognized standard ISO 15189, 'Medical laboratories-Particular requirements for quality and competence'. ISO 15189 requires comprehensive quality assurance. Detailed management and technical requirements are defined in the two major chapters. The management requirements address quality management including the quality policy and manual, document control, non-conformities and corrective actions, continual improvement, auditing, management review, contracts, referrals and resolution of complaints. Technical requirements include personnel competence (both technical and medical), equipment, accommodation and environment, and pre-analytical, analytical and post-analytical processes. Emphasis is placed on the particular requirements of patient care: notably sample identification and traceability, test validation and interpretation and reporting of Result s. Quality indicators must be developed to monitor contributions to patient care and continual improvement. We discuss the implementation of ISO 15189 with a specific emphasis on the PGD laboratory, highlight elements of particular importance or difficulty and provide suggestions of effective and efficient ways to obtain accreditation. The focus is on the European environment although the principles are globally applicable.

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