# Presentation: 142162

## Approaches to Providing Quality Testing for Rare Genetic Diseases

**The**

**Experience**
** ****2000-present**

## 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)

## 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 3rd party payers (health insurance) would be

## 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

## 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

## 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

## 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)

## 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

## 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)

## 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

## 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

## 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)**

##  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)**

##  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)**

##  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)**

## 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

**____ 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

## 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)**

## GeneDx in October 2003