Direct to Consumer Carrier Screening Brian L Shaffer MD 12/14/18 Associate Professor Maternal Fetal Medicine Doernbecher Fetal Care Clinic

Disclosures I have no relevant financial relationships

Objectives: Expanded Carrier Screening Review tenets of carrier screening ACOG: Options Ethnicity/Geographic based Standard panel Expanded carrier screening Benefits and Limitations Approach to clinical care – cases

Background: Carrier Screening – Why?

Background: Autosomal Recessive Inheritance Auto Recessive: Presence of two copies of a gene change at a particular locus in order to express a phenotype Refers to genes on one of the 22 pairs of autosomes (non-sex chromosomes)

AR conditions – relative impact

Carrier Screening – Foundations I Independent of family history: Asymptomatic If there is a family history of a condition: no longer screening Single gene: autosomal recessive; X-linked Informed consent: Non-directive - Natural history of disorder - Severity - Access to quality genetic counseling - Residual risk - Acceptance by screened population – Voluntary Relatively high frequency of carriers in population - Geographic ancestry – 1 in 30 40 min

Carrier Screening – Geographic ancestry Independent of family history: Asymptomatic Single gene: autosomal recessive; X-linked Informed consent: Non-directive - Natural history of disorder - Severity - Access to quality genetic counseling - Residual risk - Acceptance by screened population – Voluntary Relatively high frequency of carriers in population - Geographic ancestry – 1 in 30

Carrier Screening – Foundations II Quality test: Timely and dependable Inexpensive/cost efficient High detection rate – 90% Availability of intervention: Preconception/Prenatal Donor sperm/egg; PGD; adoption; forgo pregnancy Prenatal diagnosis – To carry (and prepare) or not? How often? - Once Goal: Risk assessment, informed decision making Public health implications: Prevention 30 min

Carrier Screen Strategy - ACOG Offer to those with higher prevalence - Geographic ancestry Family history – including ethnic background, consanguinity Increasingly difficult to determine an individual’s “geographic ancestry/ethnicity” Base on family history/tree? Appearance of individual and partner Admixture of population Non - paternity This approach may be less accurate/effective for carrier screening Elev FSH before 40 years

Case: 19 year old G1 8 wks, presents for OB visit Ethnicity? Geographic ancestry? Her partner is from CA No family history of any genetic disease In either she or FOB What carrier screening?

Carrier Screen Strategy - ACOG ACOG: Offer to All Cystic Fibrosis (CF) Spinal Muscular Atrophy (SMA) Hemoglobinopathy CBC – Assess MCV Electrophoresis – Low MCV or high risk ethnicity/geo ancestry Elev FSH before 40 years

Case continued Genotyping for CFTR Negative for 32 known pathogenic gene changes “So my baby won’t have cystic fibrosis” What is a residual risk? What is the risk of having an affected child? 40 min

Residual risk after negative Cystic Fibrosis: Incidence, Carrier risks and Detection rates* Group Incidence Carrier risk Detection Residual risk after negative Ashkenazi 1/2270 1/24 94% 1/384 Caucasian 1/2500 1/25 88% 1/206 Hispanic 1/13,500 1/58 72% 1/203 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

Residual risk after negative Cystic Fibrosis: Incidence, Carrier risks and Detection rates* Group Incidence Carrier risk Detection Residual risk after negative Ashkenazi 1/2270 1/24 94% 1/384 Caucasian 1/2500 1/25 88% 1/206 Hispanic 1/13,500 1/58 72% 1/203 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

Carrier Screen Strategy - ACOG ACOG: Offer to All Hemoglobinopathy CBC – Assess MCV Electrophoresis – Low MCV or high risk ethnicity/geo ancestry Sickle cell - Africa, Greek, Italian, Turkish, Arabic, Iranian, Asian Indian α Thalassemia – SE Asia, Mediterranean, Africa, West Indian β Thalassemia – Mediterranean, Asian, Middle Eastern, Hispanic, West Indian

Structure of hemoglobin Beta globin genes Alpha globin genes a1 b1 a2 b2 a3 a4 Hemoglobin protein Chromosome 11 Chromosome 16

What is her fetus at risk for? Case 2 26 yo G1P0 at 10 weeks with a younger brother with autism and cognitive disability who “looks different” than other family members. On further questioning her mother had early menopause. What is her fetus at risk for? Why the primary ovarian deficiency in her mother? What carrier screening should be offered?

Heritable cognitive disability, behavior Fragile X Syndrome Heritable cognitive disability, behavior Males (1 in 3600-4000) 2nd most common form of cognitive disability Behavior abnormalities Unique facial characteristics Females (1 in 4000-8000) If affected, usually less severe Primary ovarian deficiency Cognitive abnormalities Tremor ataxia

Fragile X – Who is at risk? Family h/o Fragile X or undiagnosed cognitive disability Known maternal premutation or full mutation Women with h/o elevated FSH or primary ovarian insufficiency of unknown etiology Family h/o primary ovarian insufficiency, tremor/ataxia Those with intermediate alleles are not at risk of having an affected child

Fragile X – Who is at risk?

Carrier Screen Strategy - ACOG ACOG: Offer to Some - Fragile X Family History of Intellectual disability Premature ovarian insufficiency / Elevated FSH (<40) ACOG: Offer to Some – Tay Sachs Ashkenazi Cajun French Canadian Elev FSH before 40 years

Carrier Screen Strategy - ACOG ACOG: Offer to Some Geographic ancestry – Eastern & Central European Jewish Descent Tay Sachs, Cystic Fibrosis Plus: Canavan disease and Familial dysautonomia Consider: Bloom, Familial hyperinsulinemia, Fanconi anemia, Gaucher, Glycogen storage disease type I, Joubert, Maple syrup urine disease, Mucolipidosis IV, Niemann-Pick, Usher…. Most would recommend NP – type A (most severe)

Carrier Screen Strategy - ACOG ACOG Additional carrier screen: Choose any Option Geographic ancestry Pan ethnic / pan geographic ancestry panel Expanded carrier screening

Carrier Screen Strategy - ACOG Pan ethnic / pan geographic ancestry panel Screened with a set panel regardless of ethnic background Several different options CF SMA Hemoglobinopathy +/- Fragile X +/- Ashkenazi (~16 additional disorders)

Expanded Carrier Screening ACOG Additional carrier screen: Choose any Option Geographic ancestry Pan ethnic / pan geographic ancestry panel Expanded carrier screening – Why? Geographic ancestry / Ethnicity based screen has limitations Recessive disorders do not occur solely in specific ethnic groups Single gene specific testing limits knowledge Many other genes with similar characteristics of CF or Sickle cell anemia

Expanded Carrier Screening Many are carriers of recessive conditions – up to 7 diseases Technology -- Next generation sequencing / High throughput genotyping Quick, inexpensive, high fidelity identification of gene changes Genotyping – Assess for a number of known changes Sequencing – Assess for changes in whole sequence or in exons

Expanded Carrier Screening – Why? Many are carriers of recessive conditions – up to 7 diseases Technology -- Next generation sequencing Quick, inexpensive, high fidelity identification of mutations Genotyping Sequencing Moore’s law is the observation that the number of transistors in a dense integrated circuit doubles about every two years

Expanded Carrier Screening Screen many genes for disease causing changes (mutations) Test ~170 genes simultaneously (~400) No longer, what can we screen for? What should we screen for? How do we decide? Impact on quality of life? Cognitive, Physical, Metabolic Timeline – Short term – Neonatal? or Life long, Age of onset Severity Variability in phenotype

Expanded Carrier Screening: Controversy Issue Potential Solution Which conditions? Severity Organ(s) affected Variability in phenotype Age of onset Most patients at risk: PNDx Conditions that have: Mild phenotype Variable expressivity Incomplete penetrance OPTIONAL Adult onset Impact on fetal offspring -- Provide Specific consent

Expanded Carrier Screening: Controversy Issue Potential Solution For a given disorder: - Causative gene - Mutation - Frequencies Residual risk calculation - Carrier frequency - Allele frequency Risk is less? - By how much Doctor? Laboratories: - Report residual risk - How risk was calculated - High detection rate

Expanded Carrier Screening: Controversy Issue Potential Solution Quality test Genotype-Phenotype For a mutation - Mild-severe? - Uncertain? Laboratories should provide citation regarding the typical clinical course

Expanded Carrier Screening: Controversy Issue Potential Solution Informed consent can’t be adequately obtained Alter the process Undergo general pre-test counseling for both partners Detailed post test counseling - Risk 1 in 4 - Residual risk

Expanded Carrier Screening: Pre Test Counseling All individuals are offered screening for the same set of conditions Impractical and unnecessary to describe all of the clinical characteristics of each condition Pretest: Broadly describe conditions – many have common features Cognitive impairment Decreased life expectancy Medical & Surgical intervention Limitations: some conditions have poorly defined phenotypes Risk assessment depends on accurate paternity

Pre-test Counseling Conditions are rare: Prevalence, mutation frequency and detection rates - imprecise Residual risk will be lower – but maybe imprecise Screen negative – “lowers but can’t eliminate risk” Panels and techniques will change – No need to repeat It is common to identify carriers – expect it! Rare: find mild presentation of recessive condition

Pretest Counseling Majority of conditions are AR, some are X-linked and AD Sequencing/genotyping – not ideal for some Hemoglobinopathy screening should be done by MCV/Hgb Elec Tay Sachs- Enzyme testing (leukocyte-whole blood) is superior to genotyping in non-Ashkenazi groups Testing is voluntary

Expanded screening – What to Expect ~25% – carrier one or more conditions ~0.7% of couples have changes in the same gene CF, SMA, Smith-Lemli-Opitz syndrome, Connexin 26 Option of invasive testing May find that your patient or father of the baby has “disease” Incorrect classification of a “mutation” Reduced penetrance or variable expressivity

Expanded screening – Post test Counseling Plan for those identified as carriers Partner testing (if concurrent testing not performed) Genotyping – known pathogenic changes Sequencing – possibility of a variant if uncertain significance Formal genetic counseling In person, Phone, Telemedicine, ?Laboratory GC Provide residual risk 1 in 4 if both are carriers Pregnant: Offer prenatal diagnosis If fetus affected – counseling, options If preconception – non carrier gamete, PGD, PNDx

Summary Carrier Screening Offer 1 of 3 strategies Geographic ancestry, Pan ethnic panel or ECS Preconception period, if possible Well woman Gyn visit/ Preconception visit Perform only once Formal genetic counseling (if available) In person, phone, telemedicine

Summary: Expanded Carrier Screening Pretest education All screening is voluntary Cannot detect all genetic abnormalities Explain: types of conditions to screen for – cognitive, etc Some conditions have less well defined phenotypes Conditions are rare – may be difficult to provide: Prevalence, gene change frequency, accurate residual risk If screen negative for a condition – the residual risk is lower Screen only once Be prepared for positive results Formal GC Residual risk, Options

References Edwards JG, et al; Expanded carrier screening in reproductive medicine – Points to Consider. Obstet Gynecol 2015:653-662 ACOG committee opinion no. 690: Carrier screening in the age of genomic medicine. American College of Obstetricians and Gynecologists 2017; 129: e35-40. ACOG committee opinion no. 691: Carrier screening for genetic conditions. American College of Obstetricians and Gynecologists 2017; 129: e41-55. Grody WW, et al; ACMG Policy Statement: ACMG position statement on prenatal/preconception expanded carrier screening; Genet Med 2013.