6/6/2014 Genetic Carrier Screening: Review of the Disclosures Old, the New, and the Controversial • I have no relevant financial relationships Brian L Shaffer, MD 6/6/14 Assistant Professor Division of Maternal Fetal Medicine Oregon Health and Sciences University Carrier Screening - Foundation Objectives • Carrier Screening: Review tenets Independent of family history: Asymptomatic • ACOG recommendations – Ethnicity based screening Single gene: autosomal recessive ; X-linked • Cystic Fibrosis, Hemoglobinopathies, Ashkenazi Jewish Informed consent: Non-directive • Natural history of disorder - Severity Disorders, Fragile X, Spinal Muscular Atrophy • Access to quality genetic counseling - Residual risk • Expanded carrier screening: “Universal” • Acceptance by screened population - Voluntary • Pros and Cons High frequency of carriers in screened population • What to expect • Geographic ancestry – 1 in 30 1
6/6/2014 Case 1 Carrier Screening - Foundation 19 year old G1 8 wks, presents for new OB visit • Ethnicity? Quality test: • Timely and dependable • Geographic ancestry? • Inexpensive/cost efficient • High detection rate – 90% • Her partner is from Mexico Availability of intervention: Preconception/Prenatal • No family history of any • Donor sperm/egg; PGD; adoption; forgo pregnancy genetic disease • Prenatal diagnosis – To carry (and prepare) or not? • In either she or FOB Goal: Risk assessment, informed decision making • Carrier Screening Public health implications: Prevention Case 1 Case 1 19 year old G1 8 wks, presents for new OB visit 19 year old G1 8 wks, presents for new OB visit • Ethnicity? • Ethnicity? • Geographic ancestry? • Geographic ancestry? • Her partner is from Mexico • Her partner is from Mexico • No family history of any • No family history of any genetic disease genetic disease • In either she or FOB • In either she or FOB • Carrier Screening • Carrier Screening • “ACOG says” ACOG SAYS ? 2
6/6/2014 Case 1 19 year old G1 8 wks, presents for new OB visit Cystic Fibrosis - CFTR • Most common AR disorder among whites (1/2500-3300) • Ethnicity? • 1/25-29 with no family history is a carrier of a CF gene change • Geographic ancestry? (mutation) or variant � alters function • Her partner is from Mexico • Pulmonary disease, pancreatic insufficiency, gastrointestinal, • No family history of any infertility; normal intelligence • Life limiting – ~40 years genetic disease • In either she or FOB • ~80% of children with CF are born to parents with no prior • Carrier Screening family history of the disease • ACOG: “it is difficult to assign a single ethnicity to affected • “ACOG says” ACOG SAYS ? individuals… offer to all patients” • Cystic Fibrosis ACOG Committee Opinion #486, 2011 Case 1 (cont.) Cystic Fibrosis: Incidence, Carrier risks and Detection rates* 19 year old G1 8 wks, presents for new OB visit Carrier Residual risk Group Incidence Detection risk after negative • Carrier Screening – negative for 32 mutations • Carrier screening for a gene is needed only once Ashkenazi 1/2270 1/24 94% 1/384 Caucasian 1/2500 1/25 88% 1/206 • “So my baby won’t have cystic fibrosis” Hispanic 1/13,500 1/58 72% 1/203 • What is a residual risk? • What is the risk of having an affected child? African American 1/15,100 1/61 64% 1/171 Asian American 1/35,100 1/94 49% 1/183 * Detection rates derived from using ACMG 23 mutation panel 3
6/6/2014 Case 1 (cont.) Limitations of Cystic Fibrosis carrier screening 19 year old G1 8 wks, cystic fibrosis screening • Negative mutation analyses “reduce but do not eliminate” the • Patient: Carrier screening Negative for mutations tested chance of having an affected child • Pre-test risk: 1/25 • >1700 disease causing mutations for CF • After negative test: ~1/206 – (Residual Risk) • Mutations tested: those most frequently detected in disease • Partner: No test • Mutation frequencies vary in different ethnic/racial bkgd • Pretest partner carrier risk: 1/58 (Latin ancestry) • Sequencing of CFTR gene & deletion/duplication studies • Residual risk estimate applies when: • Risk of affected fetus is: • Family history is negative (Mom) 1/206 x (FOB) 1/58 x (Fetus inheriting both) 1/4 = 47,000 • Correct Paternity Hemoglobinopathies: CF – What to do? “ACOG says” • African Offer screening for CF to all women: • Briefly ….. • Describe phenotype • Describe inheritance • Why women test? • Describe limitations of testing • If negative “substantially reduces risk of an affected child” • Offer partner screening after discussion of results • Document discussion • Provide written materials • … Offer formal GC if patient has additional questions ACOG Practice Bulletin #78, 2007 4
6/6/2014 Hemoglobinopathies: Structure of hemoglobin “ACOG says” African Alpha globin genes Beta globin genes • Hemoglobin electrophoresis • CBC a1 b1 a2 b2 a3 a4 Hemoglobin protein Chromosome 11 ACOG SAYS ? Chromosome 16 ACOG Practice Bulletin #78, 2007 Hemoglobinopathies: Hemoglobinopathies: “ACOG says” “ACOG says” African African • Hemoglobin electrophoresis • Hemoglobin electrophoresis • CBC • CBC Mediterranean • CBC • If Anemia, MCV <80 (microcytic) • Normal iron studies (ferritin) • Hemoglobin Electrophoresis • Assess for Beta Thalassemia ACOG Practice Bulletin #78, 2007 ACOG Practice Bulletin #78, 2007 5
6/6/2014 Hemoglobinopathies: “ACOG says” African • Hemoglobin electrophoresis • CBC Mediterranean, Southeast Asian • CBC • If Anemia, MCV <80 (microcytic) • Normal iron studies (ferritin) • Hemoglobin Electrophoresis • Assess for Beta Thalassemia ACOG SAYS ? • If normal Beta and SE Asian • α thalassemia ACOG Practice Bulletin #78, 2007 Hemoglobinopathies: Comprehensive screening β thalassemia α thalassemia 6
6/6/2014 Hemoglobinopathies: Hemoglobinopathies: Comprehensive screening Comprehensive screening β thalassemia β thalassemia α thalassemia α thalassemia Hemoglobinopathies: Comprehensive screening Case 2 β thalassemia • 26 yo G1P0 at 10 weeks with a younger brother Latin, Middle Eastern, Indian, Pacific Islander, Chinese with autism and cognitive disability who “looks • If Anemia, MCV <80, normal iron different” than other family members. On further • Hemoglobin Electrophoresis questioning her mother had early menopause. α thalassemia Mediterranean (Italy, Greece), East Asia • What is her fetus at risk for? (China), Mid Eastern (Turkey, Pakistan), Central Asia (West India), African • Why the primary ovarian deficiency in her mother? • If Anemia, MCV <80, normal iron • What carrier screening should be offered? • Hemoglobin Electrophoresis nl • Molecular studies for alpha thal 7
6/6/2014 Fragile X Syndrome Case 2 • Heritable cognitive disability, behavior • Males (1 in 3600-4000) • 26 yo G1P0 at 10 weeks with a younger brother • 2 nd most common form of cognitive disability with autism and cognitive disability who “looks • Behavior abnormalities different” than other family members. On further • Unique facial characteristics questioning her mother had early menopause. • Females (1 in 4000-8000) • If affected, usually less severe • What is her fetus at risk for? • Primary ovarian deficiency • Cognitive abnormalities • Why the primary ovarian deficiency in her mother? • Tremor ataxia ACOG SAYS ? • What carrier screening should be offered? Fragile X CGG repeat expansion, risks and clinical phenotype Fragile X – Who is at risk? Phenotype CGG Risk of Methylation Mutation type trinucleotide Transmission • status ( FMRI ) Men Women Family h/o Fragile X or repeats to full mutation undiagnosed cognitive disability Normal <40 None Unmethylated • Known maternal premutation or Risk of full mutation Intermediate 41-60 transmission at Unmethylated • 56 repeats Women with h/o elevated FSH or primary ovarian insufficiency of Yes At risk for FXTS At risk for FXTS unknown etiology Premutation 60-200 Increases with Unmethylated and POF (17% by age 60) • repeat number (POF risk 21%) Family h/o primary ovarian insufficiency, tremor/ataxia Fragile X 50% with normal Approximately syndrome 100% intellect; 50% • Full Mutation >200 Methylated Those with intermediate alleles 100% with cognitive with cognitive are not at risk of having an disability disability affected child 8
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