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Bergbaum A.,Genetics Laboratories | Ogilvie C.M.,Genetics Center
Clinical Anatomy | Year: 2016

The neuro-behavioral disorder of autism was first described in the 1940s and was predicted to have a biological basis. Since that time, with the growth of genetic investigations particularly in the area of pediatric development, an increasing number of children with autism and related disorders (autistic spectrum disorders, ASD) have been the subject of genetic studies both in the clinical setting and in the wider research environment. However, a full understanding of the biological basis of ASDs has yet to be achieved. Early observations of children with chromosomal abnormalities detected by G-banded chromosome analysis (karyotyping) and in situ hybridization revealed, in some cases, ASD associated with other features arising from such an abnormality. The introduction of higher resolution techniques for whole genome screening, such as array comparative genome hybridization (aCGH), allowed smaller imbalances to be detected, some of which are now considered to represent autism susceptibility loci. In this review, we describe some of the work underpinning the conclusion that ASDs have a genetic basis; a brief history of the developments in genetic analysis tools over the last 50 years; and the most common chromosome abnormalities found in association with ASDs. Introduction of next generation sequencing (NGS) into the clinical diagnostic setting is likely to provide further insights into this complex field but will not be covered in this review. © 2016 Wiley Periodicals, Inc.


Dimitrov B.I.,Guys Hospital | Ogilvie C.,Genetics Laboratories | Wieczorek D.,University of Duisburg - Essen | Wakeling E.,North West Thames Regional Genetic Service | And 3 more authors.
American Journal of Medical Genetics, Part A | Year: 2015

Interstitial deletions of chromosome 3p14p12 are a rare chromosome rearrangement. Twenty-six patients have been reported in the literature to date, however, a specific clinical phenotype has not yet been delineated. We describe three patients (two new) with overlapping chromosome 3p14p12 deletions and review the clinical and molecular data of 11 well-characterized, published cases. These patients had a number of features in common, such as short stature, failure to thrive, facial dysmorphism, congenital heart defects, urogenital abnormalities, neurological problems, hearing loss, and global developmental delay, suggesting that the interstitial chromosome 3p14p12 deletion gives rise to a multiple congenital anomaly syndrome. Some of the patients show clinical overlap with other complex syndromes such as CHARGE syndrome. Genotype-phenotype analysis revealed candidate genes for parts of the clinical features suggesting that the 3p14 deletion is a contiguous gene syndrome. © 2015 Wiley Periodicals, Inc.


Noli L.,Kings College London | Dajani Y.,Kings College London | Capalbo A.,Center for Reproductive Medicine | Capalbo A.,Molecular Genetics Laboratory | And 8 more authors.
Human Reproduction | Year: 2015

study question: Is the quality of the human embryos generated by twinning in vitro comparable to the quality of the embryos created by fertilization? summary answer: Our data suggest that the human twin embryos created in vitro are unsuitable not only for clinical use but also for research purposes. what is known already: Pregnancy from in vitro generated monozygotic twins by embryo splitting or twinning leads to live birth of healthy animals. Similar strategies, however, have been less successful in primates. Recent reports suggest that the splitting of human embryos might result in viable, morphologically adequate blastocysts, although the qualitative analyses of the embryos created in such a way have been very limited. study design, size, duration: This study was a comparative analysis of embryos generated by twinning in vitro and the embryos created by in vitro fertilization. participants/materials, setting, methods: We analysed morphokinetics and developmental competence of 176 twin embryos created by splitting of 88 human embryos from either early (2-5 blastomeres, n 43) or late (6-10 blastomeres, n 45) cleavage stages. We compared the data with morphometrics of embryos created by in vitro fertilization and resulting in pregnancy and live birth upon single blastocyst transfer (n 42). main results and the role of chance: The morphokinetic data suggested that the human preimplantation development is subjected to a strict temporal control. Due to a 'developmental clock', the size of twin embryos was proportionate to the number of cells used for their creation. Furthermore, the first fate decision was somewhat delayed; the inner cell mass (ICM) became distinguishable later in the twin than in the normal blastocysts obtained through fertilization. If an ICM was present at all, it was small and of poor quality. The majority of the cells in the twin embryos expressed ICM and trophectoderm markers simultaneously. limitations, reasons for caution: We created monozygotic twins by blastomere separation from cleavage stage embryos. Embryo twinning by blastocyst bisection may circumvent limitations set by the developmental clock. wider implications of the findings: Taken together, our data suggest that the human twin embryos created in vitro are unsuitable not only for clinical use but also for research purposes. © The Author 2015.


Noli L.,Kings College London | Capalbo A.,Center for Reproductive Medicine | Capalbo A.,GENETYX Molecular Genetics Laboratory | Ogilvie C.,Genetics Laboratories | And 2 more authors.
Stem Cell Reports | Year: 2015

Discordant growth is a common complication of monochorionic/diamniotic pregnancies; in approximately 50% of cases, the cause is unknown. The case presented here suggests that discordant growth of monozygotic twins could start during preimplantation development. Two inner cell masses (ICMs) within the same blastocyst may originate in uneven splitting of a single "parental" ICM, or the two ICMs may be formed independently de novo. We studied the transcriptomes of two morphologically distinct ICMs within a single blastocyst using high-resolution RNA sequencing. The data indicated that the two ICM were at different stages of development; one was in the earliest stages of lineage commitment, while the other had already differentiated into epiblast and primitive endoderm. IGF1-mediated signaling is likely to play a key role in ICM growth and to be the major driver behind these differences. © 2015 The Authors.


Chambers P.A.,University of Leeds | Stead L.F.,University of Leeds | Morgan J.E.,University of Leeds | Carr I.M.,University of Leeds | And 12 more authors.
Human Mutation | Year: 2013

We describe a sensitive technique for mutation detection using clonal sequencing. We analyzed DNA extracted from 13 cancer cell lines and 35 tumor samples and applied a novel approach to identify disease-associated somatic mutations. By matching reads against an index of known variants, noise can be dramatically reduced, enabling the detection and quantification of those variants, even when they are present at less than 1% of the total sequenced population; this is comparable to, or better than, current diagnostic methods. Following the identification or exclusion of known variants, unmatched reads are grouped for BLAST searching to identify novel variants or contaminants. Known variants, novel variants, and contaminants were readily identified in tumor tissue using this approach. Our approach also enables an estimation of the per-base sequencing error rate, providing a confidence threshold for interpretation of the results in the clinic. This novel approach has immediate applicability to clinical testing for disease-associated genetic variants. © 2012 Wiley Periodicals, Inc.

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