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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?
      • 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