EUROCRAN

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EUROCRAN
Overview of EUROCRAN WP1-WP5
Michele Rubini, Ferrara, Italy
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EUROCRAN
The European Collaboration on Craniofacial
Anomalies
A project funded by the European Commission under
the Quality of Life theme of Framework Programme
V.
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EUROCRAN

• EUROCRAN has a duration of four years
• Oct. 2000 Sep.2004

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EUROCRAN
Scientists
EUROCRAN
Clinicians
EUROCRAN brings together researchers from a range
of clinical / scientific disciplines from 14
European centres with the shared aim of improving
the management and understanding of craniofacial
anomalies (CFA).
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EUROCRAN
Geneticists Clinicians
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EUROCRAN
Clinical Research
Genetics Research
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EUROCRAN
WP1
This research project of the European Framework V
programme consists of five related projects
WP2
WP3
WP1 Surgical Trial WP2 Gene / Environment
Study WP3 Chromosomal Approach to Identifying
OFC Genes WP4 Molecular Diagnosis of Monogenic
Craniofacial Anomalies WP5 Directory of
Resources
WP4
WP5
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WP1 Surgical trial for UCLP

• A multicentre randomised trial of the primary
  surgery for
• infants with complete unilateral cleft lip and
  palate is
• comparing four surgical methods in three
  concurrent trials.

WP1
Infants are currently randomised either to a
surgical method common to all three trials or the
usual local method.
Infants have been entered to the trial from 10
European centres.
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WP1 Surgical trial for UCLP
WP1
Surgeons are performing an approximately equal
number of both their usual method, and the common
method according to the randomisation scheme
maintained at the trial co-ordinating centre.
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WP1 Surgical trial for UCLP
WP1
Copies of records are being archived centrally
and a comparison of perioperative complications
are reported.
Additionally, speech and language experts have
agreed protocols for assessment including
training in cross-linguistic analysis.
Gunvor Semb , Oslo gunvor.semb_at_man.ac.uk
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WP2 Gene-Environment Interaction
WP2
Research into the causes and methods of primary
prevention of orofacial clefts
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WP2 Gene-Environment Interaction

• Common genetic polymorphisms are modifiers of
  the relationship between environmental and
  lifestyle factors in orofacial clefting

WP2

• Role of folate and its metabolism in the
  aetiology of OFC remains uncertain
• Role of lifestyle factors such as smoking and
  alcohol is unclear
• A number of candidate genes have been proposed
• In Europe there are differing gene pools and
  variation in environmental exposures

• Multidisciplinary, multi-centre collaboration
  required

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WP2 Gene-Environment Interaction
Population based multicentre case-parent triad
study looking at gene/environment and gene/gene
interaction and genetic susceptibility
polymorphisms for orofacial clefting (OFC).
WP2

• All clefts that proceed to surgery (from june
  2001)

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WP2 Gene-Environment Interaction

• Methodology
• maternal interview on diet and other exposures in
  the periconceptional period
• samples are taken from the mother, father and
  child for DNA extraction and biochemical
  analyses
• gene variant analysis

WP2
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WP2 Gene-Environment Interaction
Dublin IR (J. Scott, A. Molloy) Maternal/fetal
metabolism genes (MTHFR) nutritional factors
(folate, vitB6, vitB12, Hcy, methylmalonic acid)
Aberdeen UK (J. Little) Genes involved in the
metabolism of xenobiotics (CYP1A1, GSTM1, GSTM3
and RARA) environmental teratogens (tobacco,
alcohol, pesticides, herbicides, solvents)
Ferrara IT (M. Rubini) Developmental growth
factor genes (TGFa, TGFß3) and homeobox genes
(MSX1) environmental factors
WP2
Peter A. Mossey, Dundee, UK p.a.mossey_at_dundee.ac.u
k
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WP3 Chromosomal Approach to Identify
OFC Genes
Identification of candidate genes in CFA using
chromosomal breakpoints and deletions
WP3
In a small proportion of patients with CP or
CL/P, chromosome analysis reveals an apparently
balanced chromosome rearrangement that is not
present in either parent
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WP3 Chromosomal Approach to Identify
OFC Genes

• A cohort of European patients with OFC associated
  with apparently balanced chromosomal
  rearrangements is being identified and their
  breakpoints/clinical phenotypes catalogued.
• A bank of immortalised cell lines is being
  established from a sub-set of these patients
  where two or more instances of a specific
  breakpoint has been associated with OFC.

WP3
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WP3 Chromosomal Approach to Identify
OFC Genes

• Both high throughput molecular cytogenetic
  techniques and available sequence data from the
  Human Genome Project will be used to identify
  genes that have been interrupted by two or more
  breakpoints.
• Potentially pathogenic mutations are fully
  characterised and screened for mutations and
  polymorphisms that may be used in WP2

WP3
David Fitzpatrick, Edinburgh, UK david.fitzpatrick
_at_hgu.mrc.ac.uk
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WP4 Molecular Diagnosis of Monogenic
Craniofacial Anomalies

• Determination of the spectrum of mutations that
  underlie a number of craniofacial anomalies for
  which the gene has recently been identified
• To develop sensitive molecular assays for the
  mutations underlying a number of CFAs using
  Treacher Collins Syndrome (TCS) as a paradigm.

WP4
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WP4 Molecular Diagnosis of Monogenic
Craniofacial Anomalies

• This expertise will be disseminated to other
  molecular laboratories in the EUROCRAN group such
  that diagnostic testing will be available on a
  local basis.

• To date some 200 patients with TCS have been
  identified and samples collected.
• Mutational analysis has been carried out and 123
  mutations have been found

WP4
Mike Dixon Manchester, UK mike.dixon_at_man.ac.uk
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WP5 Directory of Resources

• Information has been gathered on
• register of clinical teams
• protocols and research interests
• governmental and non-governmental agencies
  involved in the treatment and research of CFA
• European surgical missions to developing
  countries
• model research protocols and examples of
  successful grant applications

WP5
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WP5 Directory of Resources

• GENETIC DATABASE
• emerging data from WP2 and WP3 and study
  protocols is being collected and stored in a
  database
• candidate genes
• chromosomal breakpoints

WP5
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WP5 Directory of Resources

• Good Practice Reference Archive
• a set of clinical records for consecutive cases
  of orofacial clefting is being assembled. It
  includes
• cephalometric radiographs
• dental casts
• photographs

• In addition a good practice speech interactive
  archive

WP5

• Teams will be able to compare local outcomes to
  the reference set

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WP5 Directory of Resources

• EUROCRAN Distraction Osteogenesis Study
• web based survey of the practice of distraction
  osteogenesis in Europe
• a prospective registry of complex treatment
  outcomes using distraction osteogenesis as an
  exemplar has been established
• www.eurocran.net

WP5
Anne Marie Kuijpers-Jagtman, Nijmegen,
NL A.Kuijpers-Jagtman_at_DENT.KUN.NL
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New Associated States
A proposal for funds to integrate five new
principal collaborating sites from countries of
Central and Eastern Europe has been approved.
Borut Peterlin, Lublijana, Slovenia Andrea
Sárközi, Budapest, Hungary Youri Anastassov,
Plovdiv, Bulgaria Siiri-Mai Hanstein, Tallinn,
Estonia Jan Vojtassak, Bratislava, Slovakia
NAS
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New Associated States

• The joint work includes
• Clinical outcome studies
• Gene-environment investigation
• New candidate gene identification
• Development of molecular assays for monogenic
  anomaly

NAS
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EUROCRAN website
EUROCRAN Accompanying Measures www.eurocran.org
WP6 WP7 WP8 - WP9
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EUROCRAN website

• To provide details of core protocols for
  participation of new centres
• To enable centres to compare clinical outcomes
  and prepare for partnership in future new trials
• To provide information on the progress of
  identifying genetic and environmental risk
  factors associated with CFA

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EUROCRAN website
Launch in December 2003
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EUROCRAN
WP2
WP1
WP3
NAS
WP4
WP5
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EUROCRAN
WP2
WP1
WP3
NAS
WP4
WP5
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