Impact of Genetics in Skeletal Dysplasias

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Impact of Genetics in Skeletal Dysplasias

• Ravi Savarirayan
• Head, Royal Childrens Hospital Clinical Genetics
  Unit

2
Background Timelines

• Watson and Crick, 1953
• 46 chromosomes, 1956
• Down syndrome, 1958
• DNA sequencing, 1970s
• FISH, PCR, 1980s
• Human Genome Project, 1990-2000
• Future technology (stem cells, PGD)

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Human Genome Project

• Begun in 1990 (NIH, US Dept. of Energy)
• Aim to identify all genes in human genome (around
  25 000)
• To determine human genome sequence
• Published in Nature and Science Feb. 2001
• Road map
• Medical, social, ethical, legal issues generated
• Fast-tracking elucidation of genes underlying
  various disorders

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Impact on Clinical Medicine

• Molecular confirmation of clinical diagnosis
• Ability to predict/alter natural history of
  disorder
• Accurate recurrence risk estimation
• Ability to offer prenatal (including
  preimplantation) testing
• Family (cascade) testing
• Predictive testing (asymptomatic individuals)
• Further insights into basis/heterogeneity of
  disease

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Confirmation of diagnosis

• Allows natural history to be anticipated and
  treatment instituted to prevent/minimize
  complications
• Allows genetic counselling of family for
  recurrence risks (i.e. new dominant versus
  recessive trait)

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Family (cascade) testing

• Ability to test other family members for sequence
  change (does it segregate with the phenotype?)
• Issues of family consent/family
  information/confidentiality

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Prenatal testing

• Elucidating genetic basis of a disorder does pave
  way for prenatal diagnosis
• Opens up a new area of discussion/ethical
  considerations?

8
Prenatal evaluation of suspected skeletal
dysplasias

• Prevalence of skeletal dysplasia 2-4/10000 births
• Increasingly important given escalating use of
  antenatal ultrasound
• Sentinel finding usually femur length lt5th
  centile for GA
• Specific diagnosis can be difficult antenatally

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Prenatal evaluation of suspected skeletal
dysplasias

• Largest study (Rimoin and Krakow, 1999) reported
  accurate diagnosis by referring physician in a
  third cases
• Most likely time diagnosis 18-20 weeks and late
  pregnancy
• Antenatal diagnosis of achondroplasia NOT made at
  this time

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Prenatal evaluation of suspected skeletal
dysplasias

• Two most important questions to ask in this
  situation
• Does sentinel finding indicate skeletal dysplasia
  present?
• If so, is the condition likely to be lethal or
  not?

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Prenatal evaluation of suspected skeletal
dysplasias

• Must try and distinguish between skeletal
  dysplasia and IUGR (both with short limbs)
• Indicators of lethality must be sought

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Prenatal evaluation of suspected skeletal
dysplasias

• Vital that in all cases where antenatal skeletal
  dysplasia suspected good follow up PM/clinical
  follow up of ongoing pregnancies occur to
  maximize chances for definitive diagnosis and
  benefits consequent to this (recurrence risk,
  natural history, management, prenatal molecular
  diagnosis)

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Predictive testing

• Molecular diagnosis allows identification of
  presymptomatic individuals for early testing and
  intervention
• Clinical decisions on how to manage/monitor these
  patients
• Ethical issues of testing in children

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Further insights into disease

• Enables further research into how gene change
  correlates with disease onset, severity,
  variation within and between families Facilitates
  discovery of new genes for the same phenotype
  (locus heterogeneity)
• Further insights into molecular
  pathogenesis-targets for treatment

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Further understanding of susceptibility genes

• Common sequence variants (polymorphisms) and
  their relationship to disease
• Common disease genetics
• Personalized genomics
• Interpretation of data is key

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Osteoarthritis genes

• Polymorphism in small ECM molecule (asporin)
  predisposes Japanese populations to knee and hip
  osteoarthritis
• Implications for population genetic screening,
  therapeutic management and prevention targeting
  of high risk groups

Nat Genet 37, 2005 (Kizawa et al.)
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Genes for lumbar disc disease (LDD)

• LDD caused by degeneration of intervertebral
  disks
• Common cause back pain/sciatica/spinal surgery
• Functional SNP (1184T-C) in CILP associated with
  LDD susceptibility

Seki et al., Nat Genet, June 2005
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Personalised Genomics
Disease
Environment Epigenetic factors
Phenotype Threshold
Subclinical phenotype
Genetic profile
High risk group
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The road ahead

• More diagnostic/prenatal testing options/choices
  will be available to families
• Medical conditions such as congenital hip
  dysplasia, cleft palate, limb deficiency, club
  feet will have accurate genetic markers
  identified
• Ethical issues of who will pay for this
  technology and who will decide if it to be
  employed and for whom?

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The road ahead

• More specific/confirmatory genetic tests for
  these conditions or predispositions
• Targeted anticipatory counselling regarding
  lifestyles and risk factors to avoid for certain
  predispositions (i.e. arthritis)
• Population screening for predisposition genes
  and polymorphisms
• Issues of how this will affect our lives,
  employment, insurance, marriage prospects?

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MELBOURNE BONE DYSPLASIA PROGRAM

• Clinical diagnosis/management
• Basic research
• Applied testing of new research
• Consumer input (symposia)
• Education/Counselling/Ethics-Patients
• International links for gene tests and
  collaborative clinical/molecular projects
• MCRI Theme Grant over 3 yearsIn addition to
  NHMRC Project and ARC Discovery grants

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Melbourne BONE DYSPLASIA PROGRAM
Bone Dysplasia Registry
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Orthopaedics
Genetic Counselling
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Education
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development and disease
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