10/18/2018 Disclosures Expanded Carrier Screening: What is its role in prenatal care? Nothing to disclose Teresa Sparks, MD Maternal-Fetal Medicine and Clinical Genetics University of California, San Francisco Audience poll Genetic Disease How often do you offer expanded carrier screening in your practice? 6000-7000 single gene disorders 31% 31% A. Routinely 20% of infant deaths B. Sometimes 19% 19% Every person carries on C. Rarely average 4-5 recessive lethal alleles D. Never wiringthebrain.com s y y r l e e l e e m v n r e i a t i t R N u e m o R o S 1
10/18/2018 Carrier Screening: What is the point? Carrier Screening: What is the point? Recessive disorders pass quietly through generations Usually there is no known family history of disease Unaffected carriers Affected Identify those at risk of transmitting a genetic condition Carrier Screening: What is the point? Carrier Screening: What is the point? Screening for Screening for carriers affected Counseling Assess personal beliefs, values Preconception Expanded carrier Newborn screening Carrier Screening screening Prenatal diagnosis Pre- During Anticipate Birth conception pregnancy postnatal needs Individualize Before or during management when Neonatal fetus affected pregnancy 2
10/18/2018 Good test is available Disorder is: - common - important problem - severe Intervention Natural history understood Voluntary Informed consent History of Carrier Screening Traditional Carrier Screening Hemoglobinopathies 1970’s Traditional carrier screening Tay Sachs disease 1971 Canavan disease 1998 Ancestry and family history Cystic fibrosis 2001 Small number of genetic diseases Familial dysautonomia 2004 Well-defined phenotype Spinal muscular atrophy 2008 (ACMG) ↑ prevalence in certain populations Spinal muscular atrophy 2017 (ACOG) Significantly impact quality of life Expanded Jewish panel 2008 (ACMG) → Cognitive or physical disabilities Expanded Jewish panel 2017 (ACOG) → Fetal, neonatal, early childhood onset Expanded carrier screening 2017 (ACOG) 3
10/18/2018 Traditional Career Screening: Disease Example: Tay Sachs Professional Society Recommendations Tay Sachs disease Screening should be offered to ALL women for: Lysosomal storage disease Cystic fibrosis → Hexosaminidase A deficiency Spinal muscular atrophy 2017 GM2 gangliosides neurodegeneration Thalassemias and hemoglobinopathies Offered to French Canadian, Cajun, Ashkenazi Jewish Screen with MCV for all → 1:30 of Ashkenazi Jewish descent are carriers For those with low MCV or at risk: hemoglobin electropheresis Several subtypes No treatment African, Mediterranean, Middle Eastern, Southeast Death in early childhood to later onset or cure Asian, West Indian Traditional Career Screening: Traditional Career Screening: Professional Society Recommendations Professional Society Recommendations Ashkenazi Jewish carrier screening: Screening for Fragile X should be offered when: French Canadian, Cajun, Ashkenazi Jewish Family history of Fragile X-related disorders Consider additional diseases Family history of intellectual disability Canavan disease, cystic fibrosis, familial dysautonomia, Tay Sachs disease Unexplained ovarian insufficiency or failure The 4 recommended by ACOG plus: Fanconi anemia (group C), Niemann Pick (type A,) Bloom syndrome, mucolipidosis IV, Gaucher disease 4
10/18/2018 Traditional Career Screening: Traditional Screening: Limitations Professional Society Recommendations May not optimize It is reasonable to do: knowledge Multiethnic populations Ethnicity based screening Pan-ethnic screening 2017 Expanded carrier screening Genetic conditions not isolated to populations Not a comprehensive risk assessment www.quest.com Audience poll Expanded Carrier Screening TRUE OR FALSE: Every patient considering a Advancing pregnancy or currently pregnant should be offered genetic technology expanded carrier screening. 40% 36% A. True Hundreds of genetic 24% B. False diseases simultaneously C. Undecided Who should this be offered to? e e d u s e r a l d T F c i e d n U 5
10/18/2018 Expanded Carrier Screening Next generation sequencing for hundreds of conditions simultaneously Most are full-exon sequencing Cost ~$100-350, some insurance in-network www.counsyl.com Audience poll Expanded Carrier Screening What percentage of individuals will be identified as Advantages a carrier of a genetic disease? 33% A. 10% 27% B. 22% 22% 18% C. 36% D. 45% % % % % 0 2 6 5 1 2 3 4 6
10/18/2018 Expanded Carrier Screening Expanded Carrier Screening Challenges What are the down sides? Expanded Carrier Screening Expanded Carrier Screening Disease variation in panels Uncertainties Very rare prevalence Variable phenotype Limited prognostic information Within one disease, and among all Later age of onset → Degree of impairment, etc. Minimal disease symptoms For rare diseases, less clarity about: Incomplete penetrance Prognosis Variable expression Performance of the test Screening for general population NOT recommended Carrier frequency in the population → residual risk → Genetic variants subject to interpretation 7
10/18/2018 Expanded Career Screening: Disease Example: Achromatopsia Professional Society Recommendations Achromatopsia Screening in the Age of Genomic Medicine Reduced visual acuity, nystagmus, photophobia, scotoma, partially or completely color blind Carrier frequency of at least 1/100 CNGB3, CNGA3, GNAT2, PDE6C, ATF6, or PDE6H Well-defined phenotype Detrimental effect on quality of life Non-progressive Cognitive or physical impairment, surgical or medical intervention No other organ systems affected Early onset in life Able to diagnose disease prenatally Should this really be on ECS panels? Antenatal intervention, perinatal management, etc. Expanded Career Screening: Professional Society Recommendations Position on Expanded Carrier Screening Most at-risk patients would consider prenatal diagnosis Transparency about: Incomplete penetrance, variable expressivity, mild phenotype, 6 ECS panels adult-onset Inclusion: autosomal recessive, carrier prevalence ≤1/100, carrier detection rate ≥70% Causative genes, variants, and variant frequencies known Exclusion: adult-onset, poorly studied population, unknown Validated association between variants and disease prevalence, incomplete penetrance, mild phenotype Quality control for labs 8
10/18/2018 Audience poll Expanded Carrier Screening What proportion of diseases on these panels met inclusion criteria? 55% A. 5% 39% B. 27% C. 45% D. 62% 4% 1% % % % % 5 7 5 2 2 4 6 Expanded Carrier Screening Expanded Carrier Screening PRE-test counseling Advantages: Challenges: Panethnic More carriers Equitable Counseling Many diseases Further testing Increased information Uncertainties Decision-making Variety of phenotypes Earlier diagnosis Time and cost More targeted care Anxiety First do no harm Patient preferences and beliefs 9
10/18/2018 Expanded Carrier Screening Expanded Carrier Screening PRE-test counseling Counseling is more broad: “Do you want screening to assess the risk of genetic diseases?” “Outcomes vary widely but many are serious.” “Not everything is detected by these tests.” Kraft. Genetics in Medicine. 2018. Expanded Carrier Screening Expanded Carrier Screening POST-test counseling “…..the foremost purpose of prenatal screening is not to reduce the incidence of genetic disease but to fulfill a couple’s reproductive goals.” or an individual’s Rowley, Loader and Kaplan; Am. J. Hum. Genet. 63:1160–1174, 1998 10
10/18/2018 Thank you! teresa.sparks@ucsf.edu 11
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