Expanded Carrier Screening: What s Best? James D Goldberg, MD September 17, 2017
Disclosures James D. Goldberg, M.D. Chief Medical Officer, Counsyl
3 Learning Objectives Guidelines Data Design Practice 1 2 3 4 Review current screening guidelines Examine data supporting the clinical value of expanded carrier screening (ECS) Address considerations in ECS panel design Discuss how to incorporate ECS in daily practice
4 Learning Objectives Guidelines Data Design Practice 1 2 3 4 Review recent updates in ACOG Committee Opinions Examine data supporting the clinical value of expanded carrier screening (ECS) Address considerations in ECS panel design Discuss how to incorporate ECS in daily practice
Lack of family history is misleading 5 Rare does not mean trivial: 80 % In the US, up to of children born with a genetic disease have no family history of the condition. 2 18 % of infant hospitalizations are due to genetic disease. 4 US, United States. 1. Data on file. Counsyl, 2016. 2. Blythe SA, et al. Clin Biochem. 1984;17(5):277-283. 3. Rare Diseases: Facts and Statistics. Global Genes website. https://globalgenes.org/rare-diseases-factsstatistics/. Accessed November 17, 2016. 4. Lazarin GA, et al. Semin Perinatol. 2016;40(1):29-34.
6 Two Committee Opinions on Carrier Screening 690: Carrier Screening in the Age of Genomic Medicine 691: Carrier Screening for Genetic Conditions
7 Ethnic-specific, panethnic, and expanded carrier screening are acceptable screening strategies, with counseling / education guidance and appropriate disease panel selection. (ACOG Comm Opinion No. 690)
Ethnic-specific protocol Ethnic-specific protocol 8 ACMG ACOG Caucasian Ashkenazi Jewish African/ AA Asian Hispanic Mediterr. Southeast Asian Cystic Fibrosis Spinal Muscular Atrophy Tay Sachs Disease Canavan Disease Familial Dysautonomia Bloom Syndrome Gaucher Disease Fanconi Anemia Type C Mucolipidosis IV Niemann-Pick Disease Type A Sickle Cell Anemia Thalassemia
9 It is likely that within a few decades, people will look back on our current circumstance with a sense of disbelief that we screened for so few conditions 2010 quote from Dr. Francis Collins, Director NIH
10 Learning Objectives Guidelines Data Design Practice 1 2 3 4 Review current screening guidelines Examine data supporting the clinical value of expanded carrier screening (ECS) Address considerations in ECS panel design Discuss how to incorporate ECS in daily practice
11 Landmark expanded carrier screening study Largest (n=349,790) and most diverse evaluation of the clinical value of expanded carrier screening conducted to date Haque IS, et al. JAMA. 2016;316(7):734-742.
12 Key questions How does ECS compare with current guidelinedriven screening practices in a diverse population? What are relevant metrics in evaluating carrier screening efficacy?
13 JAMA study evaluated >340,000 ethnically diverse patients 430,584 PATIENTS SCREENED 83,794 EXCLUDED Known carriers Positive family history Infertility Other n = 346,790 ROUTINE EXPANDED CARRIER SCREENING Largest, most diverse study population reported Looked at only severe & profound diseases 94 conditions *ACOG guidelines for these ethnic categories include testing for hemoglobinopathies. (HbS variants in African or African Americans including beta thalassemia and sickle cell disease, HbA variants including alpha thalassemia in Southeast Asians.) When DNA-based carrier screening for hemoglobinopathies is routinely performed, there is improved detection of at-risk pregnancies. The percentages of pregnancies affected by a non-hemoglobinopathy condition that would be missed by guidelines-based testing are: African or African-American: 82%, Southeast Asian: 81%, Southern European: 74%. Haque IS, et al. JAMA. 2016;316(7):734-742
14 Ethnicity-based guidelines miss affected pregnancies Ethnicity-based carrier screenings miss a significant percentage of pregnancies affected by serious conditions.
Affected pregnancy rates across ethnicities 15 1 in 550 pregnancies in the US are predicted to be affected Focus on affected pregnancies allows apples-to-apples comparisons
16 We already screen for conditions that are far less common Reported Incidence of Routinely Screened Conditions 2,3 1 IN 550 PREGNANCIES will be affected by a severe or profound condition on the Counsyl expanded panel 1 vs DOWN SYNDROME 1 IN 800 OPEN NEURAL TUBE DEFECTS 1 IN 1000 CYSTIC FIBROSIS 1 IN 3400 1. Data on file. Counsyl, 2016. 2. Parker SE, et al. Birth Defects Res A Clin Mol Teratol. 2010;88(12):1008-1016. 3. American Thoracic Society website. https://www.thoracic.org/patients/patient- resources/breathing-in-america/resources/chapter-7-cystic-fibrosis.pdf. Accessed November 25, 2016.
17 A clear case for ECS ECS identifies more pregnancies affected by serious conditions across ethnicities Ethnicity and family history should not be used to limit carrier screening Risk of significant number of severe and profound conditions is present across the population Standard risk assessment of serious, actionable disorders is needed for all couples Haque IS, et al. JAMA. 2016;316(7):734-742.
18 Learning Objectives Guidelines Data Design Practice 1 2 3 4 Review current screening guidelines Examine data supporting the clinical value of expanded carrier screening (ECS) Address considerations in ECS panel design Discuss how to incorporate ECS in daily practice
A blueprint for the Foresight Carrier Screen Beauchamp KA, Muzzey D, Wong KK et al. Genetics in Medicine 2017; doi:10.1038/gim.2017.69 Copyright 2017 Counsyl, Inc. Counsyl and the Counsyl logo are trademarks of Counsyl, Inc., registered in the United States. All rights reserved.
Selecting the right diseases, not simply more Reviewed >650 genes >175 diseases serious, clinically-actionable and prevalent, where the gene-level sensitivity has been maximized 1 Lazarin GA,et al. PLoS One 2014;9:e114391 Copyright 2017 Counsyl, Inc. Counsyl and the Counsyl logo are trademarks of Counsyl, Inc., registered in the United States. All rights reserved.
Maximizing detection rates through technology High detection rates are the product of 4 key methodologies: NEW FEATURE Full-exon sequencing Custom assays Panel-wide deletion calling Real-time curation provides a significant detection rate advantage over targeted sequencing for technicallychallenging, difficult-tosequence genes that substantially improve detection of ARC and select duplication calling for certain prevalent conditions to further boost sensitivity combining automation with manual investigation to classify variants Variant identification Variant interpretation Copyright 2017 Counsyl, Inc. Counsyl and the Counsyl logo are trademarks of Counsyl, Inc., registered in the United States. All rights reserved.
U.S.-weighted disease risk How does technology enable us to maximize detection of potentially affected pregnancies?
Alpha-thalassemia whole-gene deletions Identical coding sequences frequent deletions 4 copies normal 3 copies silent carrier cis trans trans trans 2 copies carrier (cis) or silent carrier (trans) 1 copy HbH affected 0 copies Hb Bart s affected
Technological advances increase carrier-couple detection single-gene, targeted genotyping
Technological advances increase carrier-couple detection multi-gene, full sequencing
Advancing detection rates further by assessing every gene for deletions Panel-wide deletion calling Across the 175+ genes on the panel, novel deletions are detected, curated, and reported if found to be deleterious, thereby raising detection rates even further Duplication calling (in addition to deletion calling) with select, prevalent disorders improves detection rates Cystic fibrosis (CF) detection rate has increased to >99% Counsyl now offers the highest detection rate available for CF Copyright 2017 Counsyl, Inc. Counsyl and the Counsyl logo are trademarks of Counsyl, Inc., registered in the United States. All rights reserved.
Technological advances increase carrier-couple detection multi-gene, full sequencing, & novel CNVs
Case Studies Northern European Hispanic East Asian
Each component of the Foresight Carrier Screen contributes to the overall detection rate Disease detection rate: Counsyl Foresight Carrier Screen vs. Targeted Genotyping * Detection of ARC is closely related to the assessed disease risk and differs primarily by counting at-risk couples rather than affected fetuses. Assumes an idealized 500-variant targeted genotyping panel with a carrier detection rate of 90% and no coverage of 21-hydroxylase-deficient congenital adrenal hyperplasia. ** Technically-challenging cases includes the following diseases: fragile X syndrome, 21-hydroxylasedeficient congenital adrenal hyperplasia, alpha thalassemia, and spinal muscular atrophy. Copyright 2017 Counsyl, Inc. Counsyl and the Counsyl logo are trademarks of Counsyl, Inc., registered in the United States. All rights reserved.
A panel with purpose: Unmatched detection of serious disorders >99% detection rates for the vast majority of genes on the panel 1 in 42 couples identified as at-risk for serious and actionable conditions Copyright 2017 Counsyl, Inc. Counsyl and the Counsyl logo are trademarks of Counsyl, Inc., registered in the United States. All rights reserved.
Why does a >99% detection rate matter? Mixed ethnicity couple? CF carrier Carrier status unknown Northern European Hispanic 1 https://www.labcorp.com/sites/testmenu/files/450020.pdf Copyright 2017 Counsyl, Inc. Counsyl and the Counsyl logo are trademarks of Counsyl, Inc., registered in the United States. All rights reserved.
32 How do we assess efficacy of carrier screening? Metric Carrier frequency Carrier couple rate At-risk couple rate Predicted affected pregnancy rate Pros Conceptually simple Can normalize across autosomal and X-linked conditions Focus on the point of carrier screening: risk of transmission of genetic conditions Cons Recessive conditions require both parents to be a carrier Key conditions do not follow simple inheritance Complex calculation
Maximizing detection rates through technology High detection rates are the product of 4 key methodologies: Full-exon sequencing Custom assays Panel-wide deletion calling Real-time curation provides a significant detection rate advantage over targeted sequencing for technicallychallenging, difficult-tosequence genes that substantially improve detection of ARC and select duplication calling for certain prevalent conditions to further boost sensitivity combining automation with manual investigation to classify variants Variant identification Variant interpretation Copyright 2017 Counsyl, Inc. Counsyl and the Counsyl logo are trademarks of Counsyl, Inc., registered in the United States. All rights reserved.
Curation according to ACMG guidelines performed in real time. Richards et al. GiM, 2015
Curation according to ACMG guidelines performed in real time. = automated = automation-assisted manual = manual ~250 curations/week Richards et al. GiM, 2015
36 Learning Objectives Guidelines Data Design Practice 1 2 3 4 Review current guidelines Examine data supporting the clinical value of expanded carrier screening (ECS) Address considerations in ECS panel design Discuss how to incorporate ECS in daily practice
Sequential Screening Targeted Mutations Screen Woman Negative Positive Finished Screen partner Negative Calculate residual reproductive risk/offer sequencing Positive Discuss reproductive options
Tandem Screening Targeted Mutations Screen woman and partner Both negative Finished Calculate residual risk/offer sequencing One positive Both positive Discuss reproductive options
Tandem Screening Sequencing Screen woman and partner Both negative Finished Finished One positive Both positive Discuss reproductive options
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