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© 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Carrier Screening in ART 2014 Stephanie Hallam, PhD, FACMG, MBA.

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Presentation on theme: "© 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Carrier Screening in ART 2014 Stephanie Hallam, PhD, FACMG, MBA."— Presentation transcript:

1 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Carrier Screening in ART 2014 Stephanie Hallam, PhD, FACMG, MBA VP Laboratory Operations & Medical Director, Good Start Genetics The Value of Next-Generation DNA Sequencing 1

2 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Need for Carrier Screening Responsible Approach -Clinically relevant tests -Best in class technologies The Need for Accurate Screening Value of Next-Generation Sequencing Technology Clinical Experience -Clinical benefits of sequencing-based assay Agenda 2

3 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION The Need for Carrier Screening 3

4 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Importance of Carrier Screening 4 Recommended by leading medical societies ­ACOG ­ASRM ­ACMG ­Jewish advocacy organizations (e.g., NTSAD)  Disorders should be prevalent, have severe forms, and be costly to treat

5 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION The Need for Better Screening 5 1/100 babies are born with an inherited disease % of all infant deaths are due to genetic disorders % of pediatric hospital admissions are for children with genetic disorders 3 1 Monogenic disorders, World Health Organization 2 Berry, et al, Scriver, et al, Kaback, et al, 2000 Preconception screening for disease-causing mutations and genetic counseling for carriers can reduce the incidence of these diseases Incidence of Tay Sachs disease was reduced by 90% in AJ due to awareness and screening 4

6 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION CF is the most common life- threatening, genetic disorder in Caucasians Despite widespread availability of carrier screening, more than 2,500 babies are born with cystic fibrosis each year The average survival age is late 30’s¹ Individuals with CF endure chronic symptoms with lifetime treatment costs estimated over $2,000,000¹ 1 in 25 Caucasians is a carrier of CF ¹CF foundation website Cystic Fibrosis (CF) 6

7 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION SMA is the leading genetic cause of death in infants and toddlers. 1/6,000 to 1/10,000 children are born with the disease The most severe form (Type I) manifests before 6 months of age and generally results in death before age two One in 40 to one in 50 people (approximately 6 million Americans) are carriers of the SMA gene. Data from SMA foundation website Spinal Muscular Atrophy (SMA) 7 Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disease characterized by muscle atrophy and weakness.

8 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Helps determine risk for conceiving a child with an inherited disease About 1 in 16 Caucasians is a carrier for cystic fibrosis or spinal muscular atrophy, the most common autosomal recessive diseases. Preconception carrier screening for pathogenic gene mutations and genetic counseling can reduce the incidence of disease Fragile x syndrome does not follow this inheritance pattern. Carrier Screening: Assessing Inherited Disease in Couples 8

9 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Pre-Pregnancy Screening Multiple options Proceed at-risk Prenatal testing IVF with pre- implantation genetic diagnosis (PGD) of embryos Sperm or egg donation Adoption Prenatal Screening Preparation, genetic counseling, support groups Newborn Screening Early detection enabling early treatment, genetic counselor, support groups Pre-Pregnancy Screening Provides Valuable Early Information 9

10 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION 10 Responsible Approach

11 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Testing for society guideline recommended disorders using a comprehensive set of disease-causing mutations Society Guideline Recommended Disorders Disease- Causing Mutations Balance drives clinical value and sets the new standard for excellence Prevalent & Severe Validated Pathogenicity A Balanced Approach to Genetic Screening 11

12 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION * Recommended if indicated by family history ** Recommended for individuals of French Canadian or Cajun descent AJ – Tests recommended by national Jewish advocacy societies. Focus on society-recommended disorders: -Provides clinicians confidence that they are screening for relevant diseases -Assures payers that testing is justifiable Jewish Societies Guideline and Society-Recommended Disorders 12

13 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION The Best Technology for Each Test 13 Test Methodology Disorder(s) Next-Generation DNA Sequencing (comprehensive) Bloom’s syndromeGlycogen storage disease 1a Canavan diseaseMaple syrup urine disease 1A/1B Cystic fibrosisMucolipidosis type IV DLD deficiencyNiemann-Pick type A/B Familial dysautonomiaTay-Sachs disease Familial hyperinsulinismUsher syndrome type 1F Fanconi anemia group CUsher syndrome type III Next-Generation DNA Sequencing Joubert syndrome 2 (targeted) Walker-Warburg syndrome Multiplex Ligation-Dependent Probe Amplification (MLPA) Alpha-thalassemia Spinal muscular atrophy (SMA) Tri-Nucleotide Repeat PCR & Fragile X syndrome Methylation Analysis Enzyme Analysis Tay-Sachs disease (Hex A) Hemoglobin Capillary Electrophoresis Beta-thalassemia Sickle cell disease Genotyping Gaucher disease Nemaline myopathy

14 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION 14 The Need for Accurate Screening

15 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Why is Accurate Screening Important? 15 Screen with ~100 mutations Result = Negative Not tested because partner is negative

16 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Why is Accurate Screening Important? 16 Child affected with cystic fibrosis

17 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Why is Accurate Screening Important? 17 Carrier of a rare mutation, not detected by test that was used Carrier of a common mutation, but not tested

18 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Why is Accurate Screening Important? 18 Carrier identified by test with higher detection rate 1 in 4 chance for each pregnancy to be affected Carrier identified because his partner screened positive Reproductive Options Available

19 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Next-Generation DNA Sequencing 19

20 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. DNA Sequencing: The “Old” Way First human genome ­~13 years ­~ $3B At completion, cost to repeat was $300M Routine clinical sequencing was unaffordable

21 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. Next-Generation DNA Sequencing Massively parallel chemistry and detection ­Faster ­Cheaper Revolutionizing Clinical Molecular Testing

22 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Next-Generation Sequencing: Technology Matters 22 Genotyping Used by many companies for routine carrier screening Tests for a limited set of only common mutations Provides limited utility beyond Caucasian and Jewish ethnicities Next-Generation Sequencing Comprehensively evaluates the gene Detects all known common and rare disease-causing mutations Delivers higher accuracy across ethnicities

23 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Delivering Clinically Actionable Results Rigorous, multi-year process to catalogue and evaluate each gene for all documented disease-causing variants Accurate, actionable results that do not include variants of unknown significance (VUS) Comprehensive Set of Known Disease-Causing Mutations 23

24 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Evaluating Variants: Not all are pathogenic 24 Some have no detrimental effect Some have a mild effect Some cause severe disease

25 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION >2,700 variants Literature (PubMed) Locus Specific Databases >2,700 variants Literature (PubMed) Locus Specific Databases ~1,000 variants classified as disease-causing Genetic Evidence Experimental Evidence Sequence Based Evidence ~ 1,700 variants Mutation Database: Validating the Variants 25

26 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Each dot represents a disease-causing mutation. (illustrative purposes only) ACMG 23 Standard genotype screening panels (≈100) Previously publicly reported pathogenic mutations (550) Novel truncating mutations detectable by next-generation DNA sequencing (unknown) GoodStart Select™ detects all of the disease-causing mutations above NGS Versus Genotyping: Mutations in the CFTR Gene 26

27 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION NGS Tests for 5-10 Times More Pathogenic Mutations Per Disease than traditional genotyping DISEASE CARRIER FREQUENCY * LEADING COMPETITORS GOOD START GENETICS Bloom's Syndrome1 in Canavan Disease1 in Cystic Fibrosis1 in 23~ Dihydrolipoamide Dehydrogenase Deficiency1 in Familial Dysautonomia1 in Familial Hyperinsulinism1 in Fanconi Anemia Group C1 in Glycogen Storage Disease Type 1A1 in Maple Syrup Urine Disease Type 1A/1B1 in Mucolipidosis Type IV1 in 8929 Niemann-Pick Disease Type A/B1 in Tay-Sachs Disease1 in Usher Syndrome 1F1 in Usher Syndrome III1 in The Power of Sequencing 27 1 Data on file as of 12/ Third mutation reported by one competitor not confirmed by GSG to be of clinical significance. 3 According to most-recently updated version of the GSG mutation list (9/13/2013). * Based on Ashkenazi Jewish population (population selected because figures are available for all disorders). Updated 5/2014

28 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION 28 Common Mutations Uncommon Mutations High frequency Previously reported in the literature Mutations Reported In Validated Database

29 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION 29 Carrier screening by genotyping Mutations Reported Traditional genotyping tests for a limited set of mutations. Common Mutations Uncommon Mutations

30 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION 30 Uncommon Mutations Novel Mutations Mutations Reported Carrier screening by next-generation DNA sequencing Truncating mutations expected to disrupt protein function Any two mutations from the same disorder can cause disease Good Start’s NGS test for 5-10 times more mutations than carrier screening tests performed by genotyping. Common Mutations

31 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION *Data presented at the 2013 Annual Meeting of the Pacific Coast Reproductive Society NGS enables the discovery of rare and novel mutations in a pan-ethnic population Normal working protein Truncating Mutation Protein is cut off and does not work properly Normal Definition of Novel: Not yet described in the literature Disrupts protein structure and will cause disease Case Study: New CFTR Mutation Found Using NGS Detection of New Pathogenic Mutations 31

32 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Clinical Experience 32

33 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION 22,296 patients from infertility centers across the US Screened for up to 14 disorders using next-generation DNA sequencing Carrier status determined by the presence or absence of a pathogenic mutation Analysis of results: Good Start’s NGS versus genotyping-based carrier screening tests Self-reported Ethnicity % of Total Caucasian44.7% Not Provided29.0% African American7.0% Asian6.3% Hispanic5.8% Other4.8% Ashkenazi Jewish2.5% Clinical Experience 33 Data up to 1/31/2014.

34 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION ~12% of carriers would not have been identified using genotyping- based carrier screening 1,2 Carriers Detected 34 Carriers Detected Gene Genotyping AssaysGSG Only Total Carriers Familial Hyperinsulinism Canavan Disease Maple Syrup Urine Disease Type 1A/1B Bloom Syndrome Cystic Fibrosis Usher Syndrome Type III 9413 Dihydrolipoamide Dehydrogenase Deficiency Fanconi Anemia Group C Glycogen Storage Disease Type 1a Tay-Sachs Disease Familial Dysautonomia Mucolipidosis Type 1V Usher Syndrome Type IF Niemann-Pick Disease Type A/B Total – Results based on analysis of 22,296 patients in IVF centers across the country screened for up to 14 disorders using GoodStart Select. 2 – Analysis was done by comparing the mutations found using GoodStart Select to competitors’ genotyping panels. If all competitors did not test for a particular mutation, then it was marked as GSG only.

35 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION Reduce the risk of having a child with a common, severe genetic disorder Clinical Implications of NGS for Your Patients 35 High detection rate, regardless of ethnicity Low residual risk, regardless of ethnicity Confidence in a negative test result

36 © 2014 Good Start Genetics, Inc. All rights reserved. Confidential. NOT FOR DISTRIBUTION 36 Thank You!


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