genetic inter university course 2016 yves sznajer - beshg · inter university course 2016 yves...
Post on 30-Apr-2018
216 Views
Preview:
TRANSCRIPT
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
2
Cliniques universitaires Saint-‐Luc – Nom de l’orateur
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
Cliniques universitaires Saint-‐Luc – Nom de l’orateur
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
Cliniques universitaires Saint-‐Luc – Nom de l’orateur
hDp://www.eurocat-‐network.eu
5
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
Cliniques universitaires Saint-‐Luc – Nom de l’orateur
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
Cliniques universitaires Saint-‐Luc – Nom de l’orateur
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
Cliniques universitaires Saint-‐Luc – Yves Sznajer 19 02 2016
Comparable ?
British Journal of Obstetrics and Gynecology 2008;115:689-696
Cliniques universitaires Saint-‐Luc – Yves Sznajer 19 02 2016
Comparable…
British Journal of Obstetrics and Gynecology 2008;115:689-696
Cliniques universitaires Saint-‐Luc – Yves Sznajer 19 02 2016
Birth defect – baseline approach
Prevalence Birth defect 3%
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
Cliniques universitaires Saint-‐Luc – Yves Sznajer 19 02 2016
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)
Cliniques universitaires Saint-‐Luc – Yves Sznajer 19 02 2016
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
Cliniques universitaires Saint-‐Luc – Yves Sznajer 19 02 2016
Path for reasoning
Clinical feature congenital/birth defect
Syndrome IdenFficaFon
CytogeneFc Gene(s -‐ Cell biology and pathway
Cliniques universitaires Saint-‐Luc – Yves Sznajer 19 02 2016
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
Cliniques universitaires Saint-‐Luc – Yves Sznajer 19 02 2016
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
Cliniques universitaires Saint-‐Luc – Yves Sznajer 19 02 2016
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
Cliniques universitaires Saint-‐Luc – Nom de l’orateur
KNOWLEDGE FROM PHENOTYPES…
Noonan JA. and Lexington K. Am J Dis Child 1968,116:373-380
Cliniques universitaires Saint-‐Luc – Nom de l’orateur
…To GENOTYPE – RASopathies Conditions from MAP KINASE pathway
Legius syndrome
Cliniques universitaires Saint-‐Luc – Nom de l’orateur
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
Cliniques universitaires Saint-‐Luc – Yves Sznajer 19 02 2016
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
Cliniques universitaires Saint-‐Luc – Nom de l’orateur
Suggested Readings
34
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.
top related