Impact of Genetics in Skeletal Dysplasias
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Impact of Genetics in Skeletal Dysplasias

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  • Ravi

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  • 1. Impact of Genetics in Skeletal Dysplasias Ravi Savarirayan Head, Royal Children’s Hospital Clinical Genetics Unit
  • 2. Background: Timelines
    • Watson and Crick, 1953
    • 46 chromosomes, 1956
    • Down syndrome, 1958
    • DNA sequencing, 1970’s
    • FISH, PCR, 1980’s
    • Human Genome Project, 1990-2000
    • Future technology (stem cells, PGD)
  • 3. 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
  • 4. 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
  • 5. 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)
  • 6. 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
  • 7. 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 <5th centile for GA
    • Specific diagnosis can be difficult antenatally
  • 9. 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
  • 10. 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?
  • 11. 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
  • 12. 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)
  • 13. 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
  • 14. 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
  • 15. Further understanding of “susceptibility” genes
    • Common sequence variants (polymorphisms) and their relationship to disease
    • Common disease genetics
    • “ Personalized genomics”
    • Interpretation of data is key
  • 16. 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.)
  • 17. “ 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
  • 18. “Personalised Genomics” Genetic profile Environment Epigenetic factors Subclinical phenotype Disease Phenotype Threshold High risk group
  • 19. 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?
  • 20. 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?
  • 21. 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 years In addition to NHMRC Project and ARC Discovery grants
  • 22. Melbourne BONE DYSPLASIA PROGRAM Dentistry Molecular Genetics Laboratory Bone & cartilage development and disease Commercial Partner Cartilage & Bone Regeneration Program Biomaterial development Bone Dysplasia Registry Orthopaedics Genetic Counselling Education Ethics Molecular Diagnosis Laboratory Endocrinology