genetic inter university course 2016 yves sznajer - beshg · inter university course 2016 yves...

Genetic Inter University

Course 2016

Yves Sznajer

Centre de génétique humaine

Feb 19th

Cliniques universitaires Saint-‐Luc – Nom de l’orateur

Plan of the presenta.on Development Gene.cs and Birth defects

Refer to Thompson/Thompson Textbook Chapter 14 8th Ed. RaFonale in medical geneFcs DefiniFons and nosology Epidemiology -‐ Database DisFnct approaches: Syndromology

Dysmorphology Development biology

Suggested readings

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Ra.onale Clinical geneFcist seeks a consistent approach to the diagnosFc process in a paFent with birth defect Evidence extracted from -‐  Embryology Integrate mechanisms leading to normal

human development on the one single paFent

-‐  When appropriate Epidemiology – PopulaFon GeneFcs Animal models (ortholog)

-‐  Aims DiagnosFc assessment Precise delineaFon on natural history prognosis, recommendaFon on follow-‐up Precise geneFc counselling


Tool I -‐ Congenital Anomalies Registries Specific public health problem indicators

EUROCAT European network for the surveillance of congenital anomalies -‐ tribute to Prof Y Gillerot Central Registry – Project Management Commi[ee Reliable, Available and Comparable on quan.ta.ve or qualita.ve parameters -‐ Dataset Registries

European community Health indicators: 4 core indicators covering demographic, socio-‐economic, health determinants, health status, intervenFons and services

h[p://ec.europa.eu/health/indicators/echu/ index_eu.html


hDp://www.eurocat-‐network.eu

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Search Type: Anomaly Registry Free Text

Select an anomaly...

Home Member Login Members Forum Sitemap

Where Am I? -> Home PageDirect link to this page: http://www.eurocat-network.eu/homepage

Announcements [Archive Announcements] Keep the dates! The 31th EUROCAT Registry Leaders’ Meeting will be organised by the European Commission's Joint Research Centre (JRC)-Ispra on 15thand 16th (am) June 2016 in Baveno, Lago Maggiore District, Italy. The 13th EUROCAT Scientific Symposium will be organised on 16th (pm) and 17th (am) June 2016 in the same location. Details of theprogramme will be released soon. A call for abstracts will be organised. The publication of the abstracts is planned. JRC-EUROCAT Central Registry is processing 2015 data submission.EUROCAT prevalence tables will be published on the website in the first quarter of 2016. Recent EUROCAT publication in The BMJ: Long term trends in prevalence of neural tube defects in Europe: population based study.http://www.bmj.com/cgi/doi/10.1136/bmj.h5949 Related Editorial in the BMJ: Folic acid fortification for Europe?http://www.bmj.com/cgi/doi/10.1136/bmj.h6198 The BMJ Press Release (25 November 2015)European folic acid policy is failing to prevent many neural tube defects, warn experts.Study finds no clear evidence of a downward trend in neural tube defects over 20 year period. http://bmjcom.c.presscdn.com/company/wp-content/uploads/2015/11/folic-acid.pdf

"EUROCAT receives funding from the European Union, in the framework of the Public Health Programme""EUROCAT is a WHO Collaborating Centre for the Surveillance of Congenital Anomalies"

Website created and hosted by

Copyright Statement | General Disclaimer

ABOUT USWhat Is EUROCAT?EU Rare Diseases PolicyMember RegistriesData CollectionRequesting EUROCAT DataPublications

CODING & CLASSIFICATIONCoding Committee

ACCESS PREVALENCE DATAPrevalence TablesKey Public Health IndicatorsInterpretation Guide

PREVENTION & RISK FACTORSPrimary PreventionFolic AcidMedication During PregnancyEnvironmental Pollution

PRENATAL SCREENING &DIAGNOSIS

General InformationPrenatal Detection (PD) Rates

CLUSTERS & TRENDSStatistical Monitoring

USEFUL LINKS

CONTACT US

GALLERYLast update 11 2014


Tool I -‐ Congenital Anomalies (CA) Registries

The Objec.ves of EUROCAT

-‐ provide essenFal epidemiologic informaFon on CA in Europe -‐ facilitate the early warning of new teratogenic exposures -‐ evaluate the effecFveness of primary prevenFon -‐ assess the impact of developments in prenatal screening -‐ act as an informaFon and resource center for the populaFon, health professionals and managers regarding clusters or exposures or risk factors of concern

-‐ provide a ready collaboraFve network and infrastructure for research related to the causes and prevenFon of congenital anomalies and the treatment and care of affected children

-‐ act as a catalyst for the se`ng up of registries throughout Europe collecFng comparable, standardised data


Selected Categories (6)

1 Perinatal mortality due to congenital anomaly > prenatal 20st weeks Fll postnatal 1st week /1000 births

2 Congenital anomaly prenatal diagnosis prevalence

3 Congenital anomaly terminaFon of pregnancy

4 Down syndrome birth prevalence

5 Congenital anomaly pediatric surgery

6 Neural tube defect total prevalence


Congenital anomalies - Prevalence - Data


Selected Categories

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Selected Categories

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Cliniques universitaires Saint-‐Luc – Yves Sznajer 19 02 2016

Selected Categories

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Comparable ?

British Journal of Obstetrics and Gynecology 2008;115:689-696


Comparable…

British Journal of Obstetrics and Gynecology 2008;115:689-696


Birth defect -‐ Causes

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Birth defect – baseline approach

Prevalence Birth defect 3%

Otherly addressed

Approach to birth defect

Prévalence

Reproduced from: New Clinical Gene.cs, 3rd edi.on Andrew Read and Dian Donnai ISBN 9781907904677 © Scion Publishing Ltd, 2015


Birth defect -‐ Nosology

Deforma.on result from extrinsic factors that modify /alter physical fetus devlpt

Disrup.on result from destrucFon of irreplaceable fetal Fssue (vascular, trauma, teratogen)

Malforma.on result from intrinsic abnormaliFes in one

or more geneFc program operaFng during development (Polydactyly)


Nosology ct’d Associa.on: similar birth defect in different embryologic

fields and inability so far to idenFfy a cause a.o. V.A.T.E.R, VACTER, VACTERL, cervico auriculo vertebral (‘Goldenhar’ )

Sequence: Pierre Robin, Po[er (a.o) Syndrome: combinaFon of birth defects that occur

secondarily to a cytogeneFc and/or a gene anomaly

Spectrum: monogenic or cytogeneFc anomaly leading to a modificaFon a signaling pathway during devlpt -‐ possibly

responsible for a wide range of signs that may be overlooked as disFnct


Path for reasoning

Clinical feature congenital/birth defect

Syndrome IdenFficaFon

CytogeneFc Gene(s -‐ Cell biology and pathway


Tool II Clinical approach – Dysmorphology

David Smith’s contribuFon in 1966 Understand contribuFon of both abnormal geneFc and non geneFc, environmental factors that influence birth defect occurrence Dysmorphologist diagnoses a child with a birth defect, suggests apropriate work-‐up, guarantees follow-‐up and integrates pedigree and family history to published clinical reports to basic science literature InteracFons with specified (sub) specialists and allied heatlh care to provide care


International group of clinicians working in dysmorphology Aims: initiated the standardization of terms used to describe human morphology; reach consensus regarding their definitions; increase the utility of descriptions of the human phenotype and facilitate reliable comparisons of findings among patients - Improve discussions with other related workers (pathologists, devlpt biology, molecular genetics) which will become more precise Rationale: recommendations for the description and definitions of human phenotypic variations the same way ISCN and human sequence variation were elaborated

Dysmorphologist’s textbook


For Head and Face For Peri orbital Region For the Ear For the Nose and Philtrum For the lip, mouth and oral region For the Hands and feet

2009;149A(1):1-127

Standard Terminology

FACIAL MORPHOLOGIC VARIATION

SYNDROME


KNOWLEDGE FROM PHENOTYPES…

Noonan JA. and Lexington K. Am J Dis Child 1968,116:373-380


KNOWLEDGE FROM PHENOTYPES…


Knowledge on evolving phenotype with age


…To GENOTYPE – RASopathies Conditions from MAP KINASE pathway

Legius syndrome


Génotype et phénotype

c.922A>G (p.N308D) PTPN11 c.305C>G (p.P102R) SOS1

RAF1

Ras-GTP

Nau

Ras-GDP

C-Raf

ERK1/2

MEK1/2

RTK

Gene expression Regulation

P P P

Y

Y

Y

SHP-2

SHP-2

Sos

Grb2

GDP

GTP GTP

GDP NF1, p120GAP

P C-Raf

MEK1/2 P

ERK1/2 P

Y Y

L SHP-2 : molecular adaptator


TOOL III Developmental biology Field of science invesFgaFng and dissecFng mechanisms of organisms development Underlying: cellular level as of enFre organ, Fssue and system

development Concepts: proliferaFon, growth, differenFaFon and apoptosis Homologous – homology if structure present in a common ancestor compare to analogous structure (‘similar’) but arose independently through different lineages (ex. wing structure) but convergent evoluFon Orthologous: idenFcal structure and genotype found in animals when

compare to Homo sapiens Chapter 3 Hum Mol Gene9cs Garland Science Ed. P. Strachan and A. Read

Cliniques universitaires Saint-‐Luc – Nom de l’orateur 32

Basic concepts of development biology Embryologic development Cellular processes during Development Morphogenesis Human Embryogenesis Fate undifferenFated cells reach their ulFmate desFnaFon SpecificaFon (differenFaFon allows disFnct cells funcFon but may sFll be influenced by environnemental factors

DeterminaFon (irreversibly acquired a[ributes)

Cliniques universitaires Saint-‐Luc – Nom de l’orateur 33

Basic concepts of development biology II Gene regulaFon by TranscripFon factors

control development by controling expression of other genes some acFvate/repress target genes Different/Specific regio / Fme to direct 3 Dimensional and Fmeline regulaFon Cell -‐ Cell signalling by direct contact and/or by morphogens InducFon of cell shape and polarity Cell movement

Apoptosis – Programmed cell death


Suggested Readings

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Andrew Read and Dian Donnai Scion Publ

« Géné.que médicale: de la biologie à la clinique » De boeck Ed. Tom Strachan and Andrew Read Human Molecular Gene.cs – 4th Ed. Garland Publ.


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