Human Genetics

& ESHG May eMagazine

1

Contents Click below to explore…

3) Introduction

4) Welcome to the Wiley booth at

ESHG!

5) Welcome to the Wiley booth at

ESHG!

6) Pain Genetics: Basic to Translational

Science

7) Genome‐wide analysis reveals a

role for BRCA1 and PALB2 in

transcriptional co‐activation

8) Cellular Reprogramming: An

Interdisciplinary View

9) Genetic Tests: Clinical Validity and

Clinical Utility

10) The marriage of Cytology and

Cytogenetics

11) From Germ Cell to Implantation –

The Epigenetic Story

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 genome-

wide association studies are mutually

exclusive in prostate cancer and

rheumatoid arthritis

14) BRCA1 and BRCA2

15) Maternally inherited genetic

variants of CADPS2 are present in

Autism Spectrum Disorders and

Intellectual Disability patients

16) Genetics and genomic medicine

around the world

17) Glioma-Associated Stem Cells: A

Novel Class of Tumor-Supporting Cells

Able to Predict Prognosis of Human

Low-Grade Gliomas

18) Evidence-based Preclinical

Medicine

2

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.

Want to stay up to date with the latest news, research, books, competitions and features in genetics?

Click to Like Click to Follow

Turn the page to discover more…

3

Follow or Like our genetics social media accounts, or choose from our eMailing lists! (To sign up for an eMail list, simply click the button below, enter your email,

select ‘Life Sciences’ and tick your topics of choice).

Click to get eMails

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.

Welcome to Wiley’s

Get the ESHG Online Stand Library

4

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:

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 wileygenetics@wiley.com, or tweet questions to

us at @WileyGenetics. Responses will be posted on the

Wiley Discussions blog (see right!)

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

5

stand at ESHG!

Get ESHG Extras

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

Wiley Discussions blog…

• 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

To receive these ‘ESHG Extras’,

simply click the button below, enter

your email address, and wait to

receive your exclusive free Extras!

Stand

no.

372

Chapter 1: How Do Pain Genes Affect

Pain Experience?

Marshall Devor

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?

Pain Genetics: Basic to

Translational Science

Inna Belfer (Editor), Luda Diatchenko (Editor)

6

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

Read More Online

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.

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.

The EMBO Journal

Genome‐wide analysis reveals a role for BRCA1

and PALB2 in transcriptional co‐activation

Alessandro Gardini et al. Read More Online

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.

7

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.

Engineered genetic information processing circuits

Hao Qi, Andrew Blanchard, and Ting Lu

WIREs Collection

Cellular Reprogramming:

An Interdisciplinary View

Read the collection online

Image: Feedback control, both positive and negative, is used

extensively in engineered genetic regulatory circuits.

8

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.

Current Protocols: Human Genetics

Genetic Tests: Clinical Validity and

Clinical Utility

Wylie Burke

9

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.

Read More Online

Abstract

“Dearly Beloved, we are gathered here to join in happy matrimony…” 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.

Cancer Cytopathology

The marriage of Cytology and Cytogenetics

Paola Dal Cin, Xiaohua Qian and

Edmund S. Cibas Read More Online

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 karyotype; 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).

10

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

… and more!

Molecular Reproduction & Development

Special Issue: From Germ Cell to Implantation –

The Epigenetic Story

Guest-edited by Rocío Melissa Rivera Read More Online

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.

11

Cancer Research UK have

devised a genius way of

crowdsourcing gene data analysis-

by embedding it in a mobile space

exploration app! Check out the

video below:

Play to Cure: Genes in Space –

help Cancer Research UK beat cancer sooner

See More Online

12

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.

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.

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.

Read More Online

13

Introduction

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.

Clinical Genetics

Special Issue: BRCA1 and BRCA2

Read More Online

14

Including:

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.

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.

EMBO Molecular Medicine

Maternally inherited genetic variants of CADPS2 are

present in Autism Spectrum Disorders and Intellectual

Disability patients

Elena Bonora et al. Read More Online

15

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

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

Molecular Genetics & Genomic Medicine

Genetics and genomic medicine around the world

Suzanne Hart and Maximilian Muenke Read More Online

16

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 glioma-

initiating 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.

STEM CELLS

Glioma-Associated Stem Cells: A Novel Class of Tumor-

Supporting Cells Able to Predict Prognosis of Human

Low-Grade Gliomas

Evgenia Bourkoula et al. Read More Online

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 c-MYC, 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. 17

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 meta-

analysis, 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

• Features protocols describing the

proposed approach for a systematic

review

Introducing…

Evidence-based Preclinical Medicine

18

Read More Online

See you at ESHG!

19