inter university course 2014 ys - beshg · 12/02/14 1 genetic inter university course 2014 yves...

12/02/14

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Genetic Inter University

Course 2014

Yves Sznajer

Centre de génétique humaine

Feb 14th

Cliniques universitaires Saint-‐Luc – Yves SZNAJER

Content of the presentation Birth defect

- Refer to Thompson & Thompson Textbook Chapter 7 -  Rationale in medical genetics -  Definitions and distinct nosology - Epidemiology - Database -  Distinct approaches: Syndromology

Dysmorphology Development biology

- Suggested readings

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Rationale

-  Clinical geneticist seeks a consistent approach to the diagnostic process in a patient with birth defect

-  Supports: Knowledge on embryology and integrated

mechanisms leading to normal human development on the one single patient

Possibly: Epidemiology and Animal models

-  Aims: Diagnostic assessment More precise delineation on natural history, prognosis, recommendation on management options Appropriate genetic counselling


Support 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 Committee Reliable, Available and Comparable on quantitative or qualitative parameters – Eurocat Std Dataset Registries

European community Health indicators: 40 core indicators covering demographic, socio-economic, health determinants, health status, interventions and services http://ec.europa.eu/health/indicators/echu/index_eu.html

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Selected Categories (6)

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

2 Congenital anomaly prenatal diagnosis prevalence

3 Congenital anomaly termination of pregnancy

4 Down syndrome birth prevalence

5 Congenital anomaly pediatric surgery

6 Neural tube defect total prevalence


Congenital anomalies - Prevalence - Data

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Selected Categories

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Selected Categories

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Selected Categories

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

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


Results – Prevalence /1.000 births

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Neural Tube Defect ~=10% decrease in 2004: 1.05 in 2008: 0.94

No change in prevalence of fetal death due to NTD

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Birth defect – baseline approach

Congenital malformation: 3% Chromosomal: 25% Monogenic: 20% Teratogen, multifactorial, Environmental


Path for reasoning

Clinical feature congenital/birth defect

Syndrome Identification

Gene development Cell biology and pathways

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Birth defect Nosology

Deformation : result from extrinsic factors that modify/alter physical fetus devlpt

Disruption : result from destruction of irreplaceable

fetal tissue (vascular,trauma, teratogen) Malformation: result from intrinsic abnormalities in one or

more genetic program operating during development (Polydactyly)


« Classification » Isolated

as oppose to Association: VATER, VACTER, VACTERL, Goldenhar or

cervico auriculo vertebral association Sequence: Pierre Robin, Potter (a.o) Syndrome: combination of birth defects that occur

secondarily to a chromosomal and/or a gene anomaly Spectrum: secondarily to modification in a chromosome

region or a gene involved in a signaling pathway during devlpt - possibly responsible for a wide range of signs that

may be overlooked as distinct entity

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Spectrum

Holoprosencephaly Sonic Hedgehoc SHH, ZIC2; PATCH

Single Incisor


Support II Dysmorphology

David Smith’s contribution in 1966 Understand contribution of both abnormal genetic and

non genetic, environmental factors that influence birth defect occurrence

Dysmorphologists: diagnose a child with a birth defect,

suggest apropriate work-up, guarantee follow-up and integrate pedigree and family history to published clinical reports to basic science literature

Interactions with specified (sub) specialists and allied heatlh care to provide care

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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

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Support III Developmental biology

Field of science investigating and dissecting mechanisms of ‘evolution’

Underlying: cellular level as of entire organ, tissue and system development

Concepts: proliferation, growth, differentiation 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 evolution Orthologous: identical structure and genotype found in animals when compare to Homo sapiens Chapter 3 Hum Mol Genetics 3d Ed. Garland

Science, Strachan and Read


Example HOX genes in limb development

Int J Dev Biol 2009;53:765-773

First described in Drosophila melanogaster: 8 genes distributed over 2 complex loci In vertebrates, HOX genes are duplicated and arranged in set of four clusters in autosomes

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Cliniques universitaires Saint-‐Luc – Yves SZNAJER 23

Mammals have - 39 HOX genes encoding transcription factors -  Clustered at four genomic loci (HoxA to HoxD) - Sequence comparison between members of the four clusters suggests that they evolved from a single ancestral cluster of genes

-  Transcribed sequentially according to their respective position within the clusters Kmita and Duboule, 2003

-  Systematic expression studies during development Kawazoe 2002; Pitera 1999; Sekimoto 1998


HOX D gene throughout different species

24 Ahn Devlpt Biol 2008;322(1):220-233

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HOX D genes and colinear regula6on

Woltering and Duboule PLOS one 2014;12(1):10001773

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Model of Colinear regula6on

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Duboule Devlpt Cell 2006;10:93-103 Duboule Science 2012 Montavon Science 2013

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All of the Hox genes have specific domains of expression along the anterior/posterior (primary) axis of the embryo Kessel and Gruss, 1990

Nelson C. et al. Devlpt 1996;122:1458


Support III Example: HOX genes clusters

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Support: HOX genes Ann Rev Genet 2011;45:145-166


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Colinear regula6on: landscape and archipelo

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Suggested Readings (a.o) Eurocat and database _ Birth defect http://ec.europa.eu/health Terminology in Dysmorphology AJMG 2009;149A(1):1-127 Chapter 3 Hum Mol Genetics 3d Ed. Garland Science, Strachan and Read HOX genes Nature 1995 Jun 22;375(6533):678-81 Sordino P, van der Hoeven F, Duboule D Cell Tissue Res 1999 Apr;296(1):19-25 Zákány J, Duboule D Nature 502,499–506 Wouter de Laat & Denis Duboule

Science. 2013 Jun 7;340(6137):1234167 Andrey G, Montavon T, Mascrez B, Gonzalez F, Noordermeer D, Leleu M, Trono D, Spitz F, Duboule D

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Multidisciplinary Comprehensive

Approach with at least 3 lines of evidence

Thank you

[email protected]

inter university course 2014 ys - beshg · 12/02/14 1 genetic inter university course 2014 yves...

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