Presentation on theme: "Carrier Screening in ART 2014"— Presentation transcript:
1 Carrier Screening in ART 2014 The Value of Next-Generation DNA SequencingStephanie Hallam, PhD, FACMG, MBAVP Laboratory Operations & Medical Director, Good Start Genetics
2 Agenda Need for Carrier Screening Responsible Approach Clinically relevant testsBest in class technologiesThe Need for Accurate ScreeningValue of Next-Generation Sequencing TechnologyClinical ExperienceClinical benefits of sequencing-based assay
4 Importance of Carrier Screening Recommended by leading medical societiesACOGASRMACMGJewish advocacy organizations (e.g., NTSAD)Disorders should be prevalent, have severe forms, and be costly to treatFor all women for all women of reproductive age
5 The Need for Better Screening 1/100 babies are born with an inherited disease120-30% of all infant deaths are due to genetic disorders211.1% of pediatric hospital admissions are for children with genetic disorders3Preconception screening for disease-causing mutations and genetic counseling for carriers can reduce the incidence of these diseasesIncidence of Tay Sachs disease was reduced by 90% in AJ due to awareness and screening41 Monogenic disorders, World Health Organization2 Berry, et al, 19873 Scriver, et al, 19734 Kaback, et al, 2000
6 Cystic Fibrosis (CF)CF is the most common life- threatening, genetic disorder in CaucasiansDespite widespread availability of carrier screening, more than 2,500 babies are born with cystic fibrosis each yearThe average survival age is late 30’s¹Individuals with CF endure chronic symptoms with lifetime treatment costs estimated over $2,000,000¹1 in 25 Caucasians is a carrier of CF¹CF foundation website
7 Spinal Muscular Atrophy (SMA) SMA is the leading genetic cause of death in infants and toddlers.1/6,000 to 1/10,000 children are born with the diseaseThe most severe form (Type I) manifests before 6 months of age and generally results in death before age twoOne in 40 to one in 50 people (approximately 6 million Americans) are carriers of the SMA gene.Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disease characterized by muscle atrophy and weakness.Data from SMA foundation website
8 Carrier Screening: Assessing Inherited Disease in Couples Helps determine risk for conceiving a child with an inherited diseaseAbout 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 diseaseFragile x syndrome does not follow this inheritance pattern.
9 Pre-Pregnancy Screening Provides Valuable Early Information Multiple optionsProceed at-riskPrenatal testingIVF with pre-implantation genetic diagnosis (PGD) of embryosSperm or egg donationAdoptionPrenatal ScreeningPreparation, genetic counseling, support groupsNewborn ScreeningEarly detection enabling early treatment, genetic counselor, support groups
11 A Balanced Approach to Genetic Screening Testing for society guideline recommended disorders using a comprehensive set of disease-causing mutationsSocietyGuideline RecommendedDisordersDisease-CausingMutationsBalance drives clinical value and sets the new standard for excellencePrevalent & SevereValidated Pathogenicity
12 Guideline and Society-Recommended Disorders Focus on society-recommended disorders:Provides clinicians confidence that they are screening for relevant diseasesAssures payers that testing is justifiableJewish SocietiesEvery test that GSG offers is recommended by either ACOG and/or ACMG and/or societies supportive of the Ashkenazi Jewish population.GSGs advisors and other opinion-leaders in the field have advised GSG to concentrate on the society-recommended disorders.Concentrating on these 22 disorders has allowed GSG to develop tests that are both highly accurate and clinically actionable.* Recommended if indicated by family history** Recommended for individuals of French Canadian or Cajun descent AJ – Tests recommended by national Jewish advocacy societies.
13 The Best Technology for Each Test Test MethodologyDisorder(s)Next-Generation DNA Sequencing (comprehensive)Bloom’s syndromeGlycogen storage disease 1aCanavan diseaseMaple syrup urine disease 1A/1BCystic fibrosisMucolipidosis type IVDLD deficiencyNiemann-Pick type A/BFamilial dysautonomiaTay-Sachs diseaseFamilial hyperinsulinismUsher syndrome type 1FFanconi anemia group CUsher syndrome type IIINext-Generation DNA SequencingJoubert syndrome 2(targeted)Walker-Warburg syndromeMultiplex Ligation-Dependent Probe Amplification (MLPA)Alpha-thalassemiaSpinal muscular atrophy (SMA)Tri-Nucleotide Repeat PCR &Fragile X syndromeMethylation AnalysisEnzyme AnalysisTay-Sachs disease (Hex A)Hemoglobin Capillary ElectrophoresisBeta-thalassemiaSickle cell diseaseGenotypingGaucher diseaseNemaline myopathy
15 Why is Accurate Screening Important? Screen with ~100 mutationsResult = NegativeNot tested because partner is negative
16 Why is Accurate Screening Important? Child affected with cystic fibrosis
17 Why is Accurate Screening Important? Carrier of a rare mutation, not detected by test that was usedCarrier of a common mutation, but not tested
18 Why is Accurate Screening Important? Carrieridentified by test with higher detection rateCarrieridentified because his partner screened positiveEmbryo1 in 4 chance for each pregnancy to be affectedReproductive Options Available
20 DNA Sequencing: The “Old” Way First human genome~13 years~ $3BAt completion, cost to repeat was $300MRoutine clinical sequencing was unaffordable
21 Next-Generation DNA Sequencing Massively parallel chemistry and detectionFasterCheaperRevolutionizing Clinical Molecular TestingHS2500 rapid run dual flowcell 2x100, 27 hrs, reagent cost
22 Next-Generation Sequencing: Technology Matters GenotypingUsed by many companies for routine carrier screeningTests for a limited set of only common mutationsProvides limited utility beyond Caucasian and Jewish ethnicitiesNext-Generation SequencingComprehensively evaluates the geneDetects all known common and rare disease-causing mutationsDelivers higher accuracy across ethnicitiesWhy what using isn’t “good enough”
23 Delivering Clinically Actionable Results Comprehensive Set of Known Disease-Causing MutationsRigorous, multi-year process to catalogue and evaluate each gene for all documented disease-causing variantsAccurate, actionable results that do not include variants of unknown significance (VUS)
24 Evaluating Variants: Not all are pathogenic Some have no detrimental effectSome have a mild effectSome cause severe disease
25 Mutation Database: Validating the Variants Literature (PubMed)Locus Specific DatabasesGenetic EvidenceExperimental EvidenceSequence Based EvidenceFocus on mutations that cause disease and clinically important. Not just what easy to detect with technology!~ 1,700 variants~1,000 variants classified as disease-causing
26 NGS Versus Genotyping: Mutations in the CFTR Gene Each dot represents a disease-causing mutation. (illustrative purposes only)ACMG 23Standard 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
27 The Power of Sequencing NGS Tests for 5-10 Times More Pathogenic Mutations Per Disease than traditional genotypingDISEASECARRIER FREQUENCY*LEADING COMPETITORSGOOD START GENETICSBloom's Syndrome1 in 1341-251Canavan Disease1 in 55444Cystic Fibrosis1 in 23~ 100560Dihydrolipoamide Dehydrogenase Deficiency1 in 1070 - 23Familial Dysautonomia1 in 312 - 322Familial Hyperinsulinism1 in 680 - 365Fanconi Anemia Group C1 in 1002 - 426Glycogen Storage Disease Type 1A1 in 642 - 1069Maple Syrup Urine Disease Type 1A/1B1 in 973 - 440Mucolipidosis Type IV1 in 899Niemann-Pick Disease Type A/B1 in 11545Tay-Sachs Disease1 in 277 - 1173Usher Syndrome 1F1 in 1470 - 116Usher Syndrome III1 in 1205131 Data on file as of 12/2013.2 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 Mutations Reported Uncommon Mutations Common Mutations High frequency Previously reported in the literatureIn Validated Database
29 Mutations ReportedTraditional genotyping tests for a limited set of mutations.Carrier screening by genotypingCommon MutationsUncommon Mutations
30 Truncating mutations expected to disrupt protein function Mutations ReportedGood Start’s NGS test for 5-10 times more mutations than carrier screening tests performed by genotyping.Carrier screening by next-generation DNA sequencingUncommon MutationsNovel MutationsCommon MutationsTruncating mutations expected to disrupt protein functionAny two mutations from the same disorder can cause disease
31 Detection of New Pathogenic Mutations NGS enables the discovery of rare and novel mutations in a pan-ethnic populationCase Study: New CFTR Mutation Found Using NGSNormalNormal working proteinTruncating MutationDefinition of Novel:Not yet described in the literatureDisrupts protein structure and will cause diseaseProtein is cut off and does not work properly*Data presented at the 2013 Annual Meeting of the Pacific Coast Reproductive Society
33 Clinical Experience22,296 patients from infertility centers across the USScreened for up to 14 disorders using next-generation DNA sequencingCarrier status determined by the presence or absence of a pathogenic mutationAnalysis of results: Good Start’s NGS versus genotyping-based carrier screening testsSelf-reported Ethnicity% of TotalCaucasian44.7%Not Provided29.0%African American7.0%Asian6.3%Hispanic5.8%Other4.8%Ashkenazi Jewish2.5%Not all sequencing is the same: anyone can buy the machine, but it is not as simple as that to have an accurate test.NGS has been used in research much longer than in a clinical setting because it is not easy to obtain the level of accuracy that is necessary for clinical use. It takes time to develop and validate to obtain that level of accuracy.Data up to 1/31/2014.
34 Carriers DetectedCarriers DetectedGeneGenotyping AssaysGSG OnlyTotal CarriersFamilial Hyperinsulinism23730Canavan Disease36642Maple Syrup Urine Disease Type 1A/1B181432Bloom Syndrome132033Cystic Fibrosis952511003Usher Syndrome Type III94Dihydrolipoamide Dehydrogenase Deficiency215Fanconi Anemia Group CGlycogen Storage Disease Type 1a541Tay-Sachs Disease87105Familial Dysautonomia3443Mucolipidosis Type 1V8Usher Syndrome Type IF1019Niemann-Pick Disease Type A/B26Total12941691463~12% of carriers would not have been identified using genotyping-based carrier screening1,2CF has higher values because (1) more patients are being screened for it (2) it has a high carrier frequency1 – 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 Clinical Implications of NGS for Your Patients Reduce the risk of having a child with a common, severe genetic disorderHigh detection rate, regardless of ethnicityLow residual risk, regardless of ethnicityConfidence in a negative test result