wwwn.cdc.gov/dls/pdf/genetics/rare_disease/RD 15 Bale.ppt

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  • 1. Approaches to Providing Quality Testing for Rare Genetic Diseases The Experience 2000-present
  • 2. Background of the Company
    • Founded by two long-time NIH researchers
      • Identified molecular basis of several rare hereditary skin disorders
      • Frustrated by inability to provide diagnostic, carrier, and prenatal testing (due to regulatory issues, lack of resources)
  • 3. Getting our ducks in a row
    • COMMERCIAL ENTITY
    • Get finances in order, find space
    • CLIA-certification and Maryland State License
    • Obtain professional liability insurance
    • Develop company website
    • Connect with GeneTests
    • Decide what our relationship to 3 rd party payers (health insurance) would be
  • 4. Development of the Test Menu
    • Initial test menu included tests for 16 rare hereditary skin disorders
    • Within 1 month, NIH researchers asked GeneDx to provide testing for a rare hereditary periodic fever syndrome
    • At three months - requests from research labs to confirm mutations in CLIA setting and provide carrier tests to family members
  • 5. Building the Test Menu
    • At the request of NIH investigators, we licensed a test for Familial Mediterranean Fever from NIH
    • Started getting requests from many researchers at the NIH (and elsewhere) to consider their favorite genes for our menu
    • Requests from patient support groups to develop testing for their disorder
  • 6. Choosing the genes to add
      • Strong evidence of clinical utility
        • High sensitivity (e.g. high percentage of individuals with the clinical diagnosis will have identifiable mutation)
      • Availability of expert clinician to serve as advisor
      • ‘ do-able’ by our methods
      • Expect minimum of 10 cases/year
      • Could be done at an affordable price for patients
        • < $3000
  • 7. Personnel
    • Clinical Director
    • (Board-certified Ph.D.-Medical Geneticist)
    • Scientific Director
    • (Molecular Biology/Genetics Ph.D.)
    • Director of Clinical Lab Operations
    • (Board-eligible Ph.D. Molecular Diagnostics)
    • Genetic Counselor (Board-certified MS, CGC)
  • 8. Services Offered
    • Diagnostic testing
    • Carrier testing
    • Pre-symptomatic testing ( Gorlin Syndrome, Multiple endocrine neoplasia 2A/FMTC, Familial Isolated hyperparathyroidism, etc., Peutz-Jeghers Syndrome, Carney Complex )
    • Custom mutation confirmation
    • Prenatal testing (on menu and custom)
    • Legal
    • Research support
    • Training
  • 9. Test Development
    • Development of information sheet and consent document
    • Review by Clinical Advisor
    • Test developed in R&D
    • Positive and negative report templates developed
    • Proficiency testing plan developed
    • Test transferred from R&D lab to clinical lab
    • Test added to GeneDx website and listed on GeneTests
    • Patient support groups/research labs notified (if relevant)
  • 10. Growth history
    • 2000 (9 months)
      • 166 tests
    • 2001
      • 470 tests
    • 2002
      • 1313 tests
    • 2003
      • 2538 tests
    • 2004
      • 924 tests in Q1
      • 4000 tests anticipated in 2004
  • 11. Problems encountered
    • Reinventing the wheel
      • consent
      • prenatal testing
      • proficiency testing
      • getting CLIA to understand what we do
    • Sky-rocketing liability insurance costs
      • $1500 in 2000  $40,000 in 2004
    • Licensing issues
    • HIPAA
      • understanding how it impacts us
  • 12. Current Test Menu
    • Congenital Ichthyoses
    • ____ Lamellar ichthyosis (TGM1)
    • ____ Sjögren-Larsson syndrome (FALDH)
    • ____ Epidermolytic hyperkeratosis (KRT1, KRT10)
    • ____ Ichthyosis bullosa of Siemens (KRT2e)
    • ____ Vohwinkel syndrome (GJB2; connexin26)
    • ____ Erythrokeratoderma variabilis (GJB3,
    • connexin31; GJB4, connexin30.3)
    • Other Keratin Disorders
    • Pachyonychia congenita
    • ____ KRT16, KRT6a (PC1)
    • ____ KRT17, KRT6b (PC2)
    • ____ Epidermolytic PPK of Vörner (KRT9)
    • ____ Unna-Thost disease (KRT1, KRT16)
    • ____ White sponge nevus (KRT4, KRT13)
    • ____ Steatocystoma multiplex (KRT17)
    • ____ Epidermolysis Bullosa Simplex (KRT5, KRT14)
  • 13. Current Test Menu
    • Ectodermal Dysplasia syndromes
    • ____ X-linked hypohidrotic ED (EDA1 aka ED1, EDA)
    • ____ Autosomal rec/dom hypohidrotic ED (EDAR)
    • ____ Clouston syndrome (GJB6, connexin30)
    • ____ Ectrodactyly-ED-Clefting (TP63, p63)
    • ____ Hay-Wells (TP63, p63)
    • Periodic Fever Syndromes
    • ____ Familial Mediterranean Fever (MEFV)
    • ____ Familial Hibernian Fever / TRAPS (TNFRSF1A)
    • ____ Hyper- IgD Syndrome (MVK)
    • ____ Muckle-Wells /Familial Cold Urticaria/NOMID (CIAS1)
  • 14. Current Test Menu
    • Immune Deficiency Disorders
    • Chronic Granulomatous Disease
    • ____ X-linked (CYBB) and common recessive (NCF1)
    • ____ Other autosomal recessive (NCF2, CYBA)
    • Severe Combined Immunodeficiency (autosomal recessive)
    • ____incl. Omenn Syndrome (RAG1 and RAG2)
    • ____Jak3 Deficiency (JAK3)
    • ____ X-linked agammaglobulinemia (BTK)
    • ____ Leukocyte Adhesion Deficiency (ITGB2)
    • Bone Marrow Failure Syndromes
    • ____ Fanconi Anemia (FANCA) cDNA sequence analysis
    • ____ Congenital amegakaryocytic thrombocytopenia (MPL)
    • ____ Shwachman-Diamond Syndrome (SBDS)
    • ____ Congenital and cyclic neutropenia (ELA2)
    • ____ Dyskeratosis Congenita, X-linked (DKC1)
    • ____ Dyskeratosis Congenita, Autosomal (hTR)
    • ____ Diamond-Blackfan anemia (RPS19)
  • 15. Current Test Menu
    • Cancer-Associated Syndromes
    • ____ Gorlin syndrome (PTCH)
    • ____ Cowden syndrome (PTEN)
    • ____ Bannayan-Riley-Ruvalcaba syndrome (PTEN)
    • ____ Multiple endocrine neoplasia type 1 (MEN1,Menin)
    • ____ Multiple endocrine nepoplasia type 2A/
    • Familial Medullary Thyroid Carcinoma (RET)
    • ____ Multiple endocrine neoplasia 2B (RET)
    • Hyperparathyroidism-Jaw Tumor Syndrome/ Parathyroid carcinoma/Familial Isolated Hyperparathyroidism (HRPT2)
    • ____ Tier 1 ___ Tier 2 ____Entire gene
    • Familial Cutaneous Malignant Melanoma
    • ____CDKN2A/ p16 ____ CDK4 ____ Both
    • ____ Peutz-Jeghers syndrome (STK11)
    • ____ Carney Complex (PRKAR1A)
  • 16.
    • Hereditary Rickets
    • ____ X-linked dominant hypophosphataemia (PHEX)
    • ____ Autosomal dom. hypophosphataemia (FGF23)
    • ____ Autosomal rec. Vit. D dependent rickets (CYP27B1)
    • Alagille Syndrome (JAG1)
    • ____ Tier 1 ____ Tier 2 if Tier 1 is negative
    • Coffin-Lowry syndrome (RSK2)
    • _____Tier 1 ____Tier 2 if Tier 1 is negative
    • Hermansky-Pudlak Syndrom (HPS1 and/or HPS3)
    • ____ HPS1 and HPS3 Puerto Rican mutations
    • ____ HPS3 Ashkenazi splice mutation
    • Hereditary multiple exostoses (EXT1 and EXT2)
    • _____ EXT1 only
    • _____ EXT2 if EXT1 is negative
    • _____ Both EXT1 and EXT2
    • Noonan Syndrome (PTPN11)
    • _____ Exons 3 and 8 only
    • _____ Remainder of gene (if 3 and 8 negative)
    • _____ Entire PTPN11 gene
    Current Test Menu
  • 17. Current Test Menu
    • Other Disorders
    • ____ Alexander Disease (GFAP)
    • ____ Androgen Insensitivity Syndrome (AR)
    • ____ Cartilage-Hair Hypoplasia (RMRP)
    • ____ Dent Disease/ X-linked rec nephrolithiasis (CLCN5)
    • ____ Dopa-Responsive Dystonia (GCH1)
    • ____ Fabry Disease (GLA)
    • ____ Hereditary angioedema (C1NH)
    • ____ Hirschsprung Disease (RET)
    • ____ Holt-Oram (TBX5)
    • ____ Holoprosencephaly (SHH, ZIC2, SIX3, TGIF)
    • ____ LEOPARD Syndrome (PTPN11, exons 7 and 12)
    • ____ Mucolipidosis Type IV (MCOLN1)
    • ____ Nemaline myopathy (ACTA1)
    • ____ Popliteal Pterygium Syndrome (IRF6)
    • ____ Pseudoachondroplasia/Mult Epiphyseal Dys (COMP)
    • ____ VanderWoude Syndrome (IRF6)
    • ____ X-linked Hydrocephalus (L1CAM)
    • ____ XY Female Gonadal Dysgenesis (SRY sequencing)
  • 18. GeneDx in October 2003