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Human Genetics & ESHG May eMagazine


Contents Click below to explore… 3) Introduction

4) Welcome to the Wiley booth at ESHG!

5) Welcome to the Wiley booth at ESHG!

12) Play to Cure: Genes in Space - help Cancer Research UK beat cancer sooner BDR Scholar Awards

13) Common genetic variants associated with disease from genomewide association studies are mutually exclusive in prostate cancer and rheumatoid arthritis

6) Pain Genetics: Basic to Translational Science

14) BRCA1 and BRCA2 7) Genome‐wide analysis reveals a role for BRCA1 and PALB2 in transcriptional co‐activation

15) Maternally inherited genetic variants of CADPS2 are present in Autism Spectrum Disorders and Intellectual Disability patients

8) Cellular Reprogramming: An Interdisciplinary View 16) Genetics and genomic medicine around the world

9) Genetic Tests: Clinical Validity and Clinical Utility

10) The marriage of Cytology and Cytogenetics

17) Glioma-Associated Stem Cells: A Novel Class of Tumor-Supporting Cells Able to Predict Prognosis of Human Low-Grade Gliomas

11) From Germ Cell to Implantation – The Epigenetic Story

18) Evidence-based Preclinical Medicine


Introduction Welcome to the May Genetics eMagazine! Are you attending (or wish you were attending) the European Human Genetics conference (May 31st – June 3rd)? In this edition, find out about how you can take part in some of our interactive conference discussions between delegates and editors, sign up to receive our online stand content, and get online ‘ESHG Extras’: daily free content on key items related to symposia. Plus, you can read about the latest research in personalised gene medicine, watch how Cancer Research UK are analysing genetic data using an iTunes space game, and more! Hope to see you at the Wiley booth soon.

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Welcome to Wiley’s Sample our content Take a break from symposia by coming down to our stand and browsing our collection of human genetics books and journals. Print copies will be available to browse, but if you want to continue reading after your visit, all our sample content is available at our online mini-library of human genetics resources. Sign up to receive this by clicking here and entering your email address:

Get the ESHG Online Stand Library

Editor Interviews During ESHG we will be interviewing Dr Karen Gripp and Professor Maurizio Genuardi. Come down to meet the editors at the Wiley stand, or send your questions for them to, or tweet questions to us at @WileyGenetics. Responses will be posted on the Wiley Discussions blog (see right!) Sunday (11:45am) Dr Karen Gripp is a board certified pediatrician and medical geneticist, Professor of Pediatrics at T. Jefferson University in Philadelphia and Chief of the Division of Medical Genetics at the A. I. du Pont Hospital for Children in Wilmington, DE. She is also an associate editor for the American Journal of Medical Genetics Part A. Monday (11:45am) Maurizio Genuardi, Full Professor of Medical Genetics and Director of the Institute of Medical Genetics at the Catholic University in Rome, has been working since 1986 in the field of inherited predisposition to cancer, contributing to the definition of the genetic bases of hereditary tumors, in particular of the colon-rectum. He is also is a Communicating Editor for the journal Human Mutation.


stand at ESHG! Giveaways We’re cutting down on paper and offering you the chance to get some exclusive human genetics content. Each day at ESHG we will be sending out emails with free articles, chapters and protocols, on the subject of symposia: •Friday 30th May: RASopathies •Saturday 31st May: Genomic Personalised Medicine •Sunday 1st June: Copy Number Variants •Monday 2nd June: Cancer Genomics

To receive these ‘ESHG Extras’, simply click the button below, enter your email address, and wait to receive your exclusive free Extras!

Get ESHG Extras

Wiley Discussions Blog We’re celebrating all things genetics on our Wiley Discussions blog…

Stand no. 372

• Take part in our video collage of all things genetics, by answering what genetics means to YOU in 1 word only! Visit the stand to record your response on our camera • Discuss key issues with other geneticists • Ask questions of leading geneticists from our journals’ editorial boards Access the blog below or use the iPad at the Wiley stand!

Find the blog here 5

Pain Genetics: Basic to Translational Science Inna Belfer (Editor), Luda Diatchenko (Editor)

Chapter 1: How Do Pain Genes Affect Pain Experience? Marshall Devor

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There is remarkable variability in the amount pain that different people experience. Variability is the rule for acute pain in response to noxious stimuli; we each have our own “pain threshold.” It is also the rule for chronic pain associated with injury and disease, even when the provoking tissue damage is identical. A dramatic example is classical trigeminal neuralgia (TN) (type 1). TN is a severe neuropathic pain condition in which sufferers report feeling intense intermittent electric shock-like pain paroxysms in the face. The underlying nerve lesion in most cases is microvascular compression of the trigeminal root near its point of entry into the brainstem. Consistent with early postmortem reports, a recent magnetic resonance imaging (MRI) study found that 17% of mature adults have the lesion (Miller et al. 2009). However, only 0.01% of people suffer from TN pain (population prevalence ca. 10/100 000; Manzoni and Torelli 2005). That is, only 1 in every 2000 people with the lesion has TN pain. What is different about those individuals whose lesion causes devastating pain?

Image: Professor Israel Lieblich (1937– 1986), a pioneer in pain genetics, was among the first to point out that data on genetic factors that influence the development of chronic pain in rodent neuropathy models “may bear on the fact that after seemingly identical nerve injuries, some humans develop chronic pain syndromes and others do not” (Inbal et al. 1980). (Courtesy of Amia Lieblich.)

Continue reading from this PDF excerpt online 6

The EMBO Journal

Genome‐wide analysis reveals a role for BRCA1 and PALB2 in transcriptional co‐activation Alessandro Gardini et al.

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Introduction Breast and ovarian cancer susceptibility genes BRCA1 and PALB2 have enigmatic roles in cellular growth and mammalian development. Although essential for growth during early developmental programs, inactivation later in adulthood results in increased growth and formation of tumors, leading to their designation as tumor suppressors. Using genome‐wide analysis derived from high‐throughput sequencing in breast epithelial cells, researchers found an intimate association between BRCA1 and PALB2 chromatin residence and genes displaying high transcriptional activity. Moreover, BRCA1 and PALB2 appeared to play a role in transcriptional responsiveness to NF‐κB, a crucial mediator of growth and inflammatory response during development and cancer.

The genes BRCA1 and PALB2 also responded to retinoic acid (RA), a growth inhibitory signal in breast cancer cells, which may constitute the basis for their tumor suppressor activity.

Image: High‐throughput sequencing reveals chromatin‐binding sites of the breast cancer tumor suppressors BRCA1 and PALB2 and suggests transcription co‐regulatory roles at a subset of genes, including NF ‐κB targets and retinoic acid‐responsive genes.

Taken together, results highlight an important role for these breast cancer proteins in the regulation of diverse growth regulatory pathways. Read more from the article online here.


WIREs Collection

Cellular Reprogramming: An Interdisciplinary View Introduction Cellular reprogramming can either be a natural process (such as adaptation to stress), or a lab-made process (such as turning creating pluripotent stem cells for disease therapy). For students and clinicians, this collection features interdisciplinary review articles from across the WIREs series on cellular reprogramming, including… Translational reprogramming in cellular stress response Botao Liu, Shu‐Bing Qian The molecular circuitry underlying pluripotency in embryonic stem cells Aryeh Warmflash, Brigitte L. Arduini, and Ali H. Brivanlou

Deciphering the complexities of human diseases and disorders by coupling induced‐pluripotent stem cells and systems genetics Wing Y. Chang et al.

Read the collection online

Engineered genetic information processing circuits Hao Qi, Andrew Blanchard, and Ting Lu

Image: Feedback control, both positive and negative, is used extensively in engineered genetic regulatory circuits.


Current Protocols: Human Genetics

Genetic Tests: Clinical Validity and Clinical Utility Wylie Burke

Introduction The sequencing of the human genome has led to an increasing array of genetic tests that are now available for use in health care. But which should clinicians and health care policymakers use? Three easy criteria exist to help make a choice: analytic validity, clinical validity, and clinical utility. Analytic validity refers to the accuracy with which a particular genetic characteristic can be identified in a given laboratory test. Technical issues arising in the evaluation of analytic validity include the specific technical requirements of the assay chosen, its reliability, the degree to which reliability varies from laboratory to laboratory, and the complexity of test interpretation. In considering test use, the clinician must also consider clinical validity and clinical utility. These test properties refer to the accuracy with which a test identifies a patient's clinical status (clinical validity) and the risks and benefits resulting from test use (clinical utility). This unit reviews the implications of these test properties for clinical practice.

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Image: Family with multiple endocrine neoplasia type 2 (MEN2). A definitive diagnosis of MEN2 can be made in the proband (arrow), on the basis of clinical findings of MEN2 (medullary thyroid cancer and hyperparathyroidism), combined with a family pedigree demonstrating autosomal dominant inheritance of the clinical problems associated with MEN2, including medullary thyroid cancer in the proband's father, and pheochromocytoma and C-cell hyperplasia (a precursor of medullary thyroid cancer) in the proband's daughter.


Cancer Cytopathology

The marriage of Cytology and Cytogenetics Paola Dal Cin, Xiaohua Qian and Edmund S. Cibas

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Abstract “Dearly Beloved, we are gathered here to join in happy matrimony‌â€? Cytology and Cytogenetics?! Could anyone imagine a more unlikely pair? Cytology: mature, established, and unpretentious; and Cytogenetics: young, hip, flirtatious. Yet friends have been noticing the growing attraction between the two in recent years; therefore, few were truly surprised when the engagement was announced. To understand the growing connection, it helps to understand the individuals a bit better. The ability of Cytogenetics to aid in the identification and precise classification of a variety of neoplasms has not gone unnoticed by Cytology. In particular, Cytology has recognized Cytogenetics as a welcome companion in the evaluation of soft tissue tumors, lymphomas, renal and urothelial tumors, and mesothelioma. This relationship requires a good understanding of the proper handling of specimens for optimal evaluation by Cytogenetics. The marriage of Cytology and Cytogenetics will likely grow stronger as more solid tumors (eg, salivary gland neoplasms) are discovered that harbor characteristic chromosomal abnormalities.

Image: Triaging cytology for cytogenetics is illustrated. The cytologic sample can be apportioned for cytogenetic analysis at several different points, depending on the cytogenetic technique used. A fresh, unfixed sample is needed for a k aryotype; this decision is best made at the time of on-site adequacy evaluation. Either fresh or fixed cells can be used for fluorescence in situ hybridization (FISH).


Molecular Reproduction & Development

Special Issue: From Germ Cell to Implantation – The Epigenetic Story Guest-edited by Rocío Melissa Rivera

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When the sperm and egg come together at fertilization, the genomes of each cell must be restructured to support embryonic development. This Special Issue: From Germ Cell to Implantation – The Epigenetic Story aims to better position researchers and students to understand the dynamic changes in the chromatin states of gametogenesis, after fertilization, and during the development of the resulting embryo. The Special Issue also provides insight to the special ways in which stem cells utilize epigenetic mechanisms to retain their characteristic potency. Including: Epigenetic regulation of genomic imprinting from germ line to preimplantation William A. MacDonald and Mellissa R.W. Mann DNA methylation and demethylation: A pathway to gametogenesis and development Wendy Dean The epigenetics of early development: Inferences from stem cells Theodore P. Rasmussen

Image: Genomic imprints are established in the germ line in part as differentially methylatedregions (gDMRs) that are maintained in the preimplantation embryo. Maternally supplied ZFP57 and its cofactor TRIM28 protect gDMRs from demethylation processes by recruiting additional epigenetic modifiers. TRIM28 (immunolabeled in red) localizes to nuclei in the mouse blastocyst. Blastocyst image provided by Michelle M. Denomme.

… and more!


Play to Cure: Genes in Space – help Cancer Research UK beat cancer sooner

Cancer Research UK have devised a genius way of crowdsourcing gene data analysisby embedding it in a mobile space exploration app! Check out the video below:

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Birth Defects Research Scholar Awards

The winners of the Birth Defects Research Distinguished Scholar Awards will be announced at this year’s Teratology Society meeting in Bellevue, USA. See here for more information on the award, awarded for overall impact of highly cited papers to the field of birth defects research.


BJU International

Common genetic variants associated with disease from genome-wide association studies are mutually exclusive in prostate cancer and rheumatoid arthritis Gisela Orozco et al.

Introduction The link between inflammation and cancer has long been reported and inflammation is thought to play a role in the pathogenesis of many cancers, including prostate cancer (PrCa). Nevertheless, very little is known regarding the underlying aetiology. Age, race and family history of PrCa remain the primary main risk factors for PrCa. The estimates from Nordic twin studies suggest that 42% of the risk could be due to genetic factors. The search for these genetic variants has led to genome-wide association studies (GWAS), which have so far reported 49 single nucleotide polymorphisms (SNPs) associated with PrCa risk. These variants alone cannot explain fully the variation of PrCa incidence seen amongst populations. Environmental factors such as the immune system and inflammation are also thought to play a key role in PrCa aetiology. Researchers aimed to ascertain if there are common genetic risk profiles that might predispose individuals to both PrCa and the autoimmune inflammatory condition, rheumatoid arthritis. These results could have potential public heath impact in terms of screening and chemoprevention.

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Clinical Genetics Special Issue: BRCA1 and BRCA2 Introduction

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For those working in hereditary breast and ovarian cancer genetics, 2014 will be a memorable year, for it marks the 20th anniversary of both the discovery of BRCA1 on chromosome 17q and of the linkage of BRCA2 to chromosome 13q. From 20 years distance, it is clear that these have been the most influential discoveries in human cancer genetics. This is because not only are they medically important discoveries, but also the identification of these two genes has had sociopolitical and cultural significance far in excess of that accorded to other cancer susceptibility genes.

Find the Special Issue on BRCA1 and BRCA2 for free here.


BRCA1 and BRCA2 – update and implications on the genetics of breast cancer: a clinical perspective WD Foulkes Health care provider recommendations for reducing cancer risks among women with a BRCA1 or BRCA2 mutation KA Metcalfe et al.

The psychological impact of breast and ovarian cancer preventive options in BRCA1 and BRCA2 mutation carriers C Borreani et al.


EMBO Molecular Medicine Maternally inherited genetic variants of CADPS2 are present in Autism Spectrum Disorders and Intellectual Disability patients Elena Bonora et al.

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Introduction Intellectual disability (ID) and autism spectrum disorders (ASDs) are complex neuropsychiatric conditions, with overlapping clinical boundaries in many patients.

Researchers identified a novel intragenic deletion of maternal origin in two siblings with mild ID and epilepsy in the CADPS2 gene, encoding for a synaptic protein involved in neurotrophin release and interaction with dopamine receptor type 2 (D2DR). Mutation screening of 223 additional patients identified a missense change of maternal origin which disrupted CADPS2/D2DR interaction. CADPS2 allelic expression was then tested in blood and different adult human brain regions, revealing that the gene was monoallelically expressed in blood and amygdala, and the expressed allele was the one of maternal origin. Cadps2 gene expression performed in mice at different developmental stages was biallelic in the postnatal and adult stages; however, a monoallelic (maternal) expression was detected in the embryonal stage, suggesting that CADPS2 is subjected to tissue‐ and temporal‐specific regulation in human and mice. This suggests that CADPS2 variants may contribute to ID/ASD development, possibly through a parent‐of‐origin effect.

Image: C.Fine mapping of CADPS2 deletion by real‐time qPCR using different probes across the region. All data were normalized using as reference 15 gene FOXP2.

Molecular Genetics & Genomic Medicine Genetics and genomic medicine around the world Suzanne Hart and Maximilian Muenke

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Introduction To focus on various aspects of genetics and genomic medicine internationally, Molecular Genetics and Genomic Medicine has begun a new article series, on ‘Genetics and genomic medicine around the world’. Why establish this feature in Molecular Genetics and Genomic Medicine now?

First, medical genetics is a global practice. Samples are sent to laboratories around the world for diagnostic testing (for example, the Genetic Testing Registry currently includes laboratories from 39 countries). Understanding clinical practice in one country may lead to altered practice in another country, which may be especially important in working with immigrant populations and understanding their views on genetics and genomics. Second, genetics continues to be a rapidly changing field in which we are now learning to interpret much larger amounts of data from next-generation sequencing. As we are coming to grips with secondary findings in developed countries, there is uncharted territory in many areas of the globe such as sub-Saharan Africa, which may not have the medical infrastructure to evaluate incidental findings.

The first articles in this series are…

Genetics and genomic medicine in Israel Joël Zlotogora Genetics and genomics in Thailand: challenges and opportunities Vorasuk Shotelersuk, Chanin Limwongse and Surakameth Mahasirimongkol


STEM CELLS Glioma-Associated Stem Cells: A Novel Class of TumorSupporting Cells Able to Predict Prognosis of Human Low-Grade Gliomas Evgenia Bourkoula et al.

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Introduction Translational medicine aims at transferring advances in basic science research into new approaches for diagnosis and treatment of diseases. Currently, low-grade gliomas (LGG) can be only partially predicted employing current state-of-the-art markers, hindering the decision-making process. To deepen comprehension on tumor heterogeneity, researchers dissected the mechanism of interaction between tumor cells and relevant components of the neoplastic environment, isolating proliferating stem cell lines from both the glioma stroma and the neoplasm. The microenvironment of both LGG and HGG hosts non-tumorigenic multipotent stem cells that can increase in vitro the biological aggressiveness of gliomainitiating cells through the release of exosomes. The clinical importance of this finding is supported by the strong prognostic value associated with the characteristics of GASC. This patient-based approach can provide a groundbreaking method to predict prognosis and to exploit novel strategies that target the tumor stroma.

Image: Pluripotent state-specific transcription factor expression. GASC express Oct-4 (green fluorescence, C, D), Nanog (red fluorescence, E, F), and Sox-2 (yellow fluorescence, G, H). In D, F, and H, nuclei are depicted by the blue fluorescence of DAPI staining. (I): Results are presented as mean ± SD. (J): Transcripts for OCT3/4, NANOG, SOX2, KLF4 cMYC, and GAPDH are present in GASC obtained from low-grade (L) and high-grade (H) glioma samples. The neuronally committed human teratocarcinoma cell line (NT2) was used as positive control.


Introducing… Evidence-based Preclinical Medicine Evidence-based Preclinical Medicine is Wiley’s newest open access journal and the first of its kind dedicated to publishing systematic review protocols and systematic reviews which summarise data from animal studies on subjects relevant to human health. Systematic reviews are a form of metaanalysis, identifying, appraising, selecting and synthesising all high quality research evidence relevant to a specific question. EBPM’s synthesis of preclinical evidence will improve evaluation of the potential success of future clinical trials, improving the reliability and value of medical research.

• Edited by Associate Professor David Howells, (Florey Institute of Neuroscience and Mental Health) and Professor Malcolm Macleod (University of Edinburgh) • Features a ‘Helpdesk’, to guide practitioners through the processes of systematic review, and to help authors prepare their study datasets for publication

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• Features protocols describing the proposed approach for a systematic review


See you at ESHG!


Human Genetics & ESHG May eMagazine  
Human Genetics & ESHG May eMagazine