12/6/19 Genomic Sequencing in Women’s Health Mary E Norton, MD Department of Obstetrics, Gynecology, and Reproductive Sciences University of California, San Francisco 1 Disclosures • Research funding from Natera • Consultant to Invitae 2 1
12/6/19 "an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.” 3 Precision Medicine 4 2
12/6/19 Precision Medicine 5 Genetics/Genomics and Women’s Health 6 3
12/6/19 Women’s Health • Screening for health risk • Cancer • Other disorders • Reproductive risk • Carrier screening • Prenatal testing 7 8 4
12/6/19 9 Direct to Consumer Genetic Testing 10 5
12/6/19 Case presentation Patient produces 23andMe document 11 Case presentation 1 12 6
12/6/19 13 23andMe Traits Reports • Freckles • Asparagus Odor Detection • Hair Curliness • Back Hair (available for • Light or Dark Hair men only) • Male Hair Loss (available • Bald Spot (available for for men only) men only) • Newborn Hair Amount • Bitter Taste Perception • Photic Sneeze Reflex • Cheek Dimples • Red Hair • Cleft Chin • Skin Pigmentation • Earlobe Type • Sweet Taste Preference • Earwax Type • Toe Length Ratio • Eye Color • Unibrow • Finger Length Ratio • Widow's Peak 14 7
12/6/19 15 23andMe Wellness Reports • Alcohol Flush Reaction • Caffeine Consumption • Deep Sleep • Lactose Intolerance • Muscle Composition • Saturated Fat and Weight • Sleep Movement 16 8
12/6/19 Case presentation 17 Case presentation 18 9
12/6/19 BRCA1/2 23andMe testing 19 BRCA1/2 23andMe testing 20 10
12/6/19 Direct to Consumer Genetic Testing Uses/ Benefits Challenges/Risks • Determine ancestry • Complex to interpret • Recruit to research • Not clinically validated studies • Privacy concerns • Assess health risks • Unexpected findings • Relatives • Entertainment • Law enforcement 21 Direct to Consumer Genetic Testing • “The test is not a substitute for visits to a healthcare professional for recommended screenings or appropriate follow-up. Results should be confirmed in a clinical setting before taking any medical action. “ 22 11
12/6/19 Is DTC testing accurate? • From 23andMe: “The raw data provided by 23andMe has undergone a general quality review; however, only a subset of markers have been individually validated for accuracy. The data from 23andMe’s Browse Raw Data feature is suitable only for informational use and not for medical, diagnostic or other use. Consult with a healthcare professional before making any major lifestyle changes.” 23 N=49 samples 24 12
12/6/19 Direct to Consumer Genetic Testing • High FP rate attributed to testing methodologies • DTC labs use SNP genotyping (coverage at only specific predetermined sites) vs. full-gene sequencing with del/dup analysis • Probe coverage varies even between DTC companies • Clinical confirmatory testing is indicated for any raw data variant Ø This is not a substitute for clinical testing! 25 The history of prenatal diagnosis has focused on Down syndrome Down syndrome Yes No Terminate pregnancy No Yes 26 13
12/6/19 Prenatal testing is increasingly complex… 27 Lejeune, 1959 Tijo and Levan, 1956 28 14
12/6/19 1979: NICHD Consensus Panel on Amniocentesis 29 1997 30 15
12/6/19 Analysis of cell free DNA 31 cfDNA screening for T21: meta-analysis cfDNA screening for T21: meta-analysis ( Gil et al, Ultrasound Obstet Gynecol, 2015 ( Gil et al, Ultrasound Obstet Gynecol, 2017) DR: 99.7% (99.1- 99.9) FPR: 0.04% (0.02 - 0.07) DR: 99.2% (98.5 - 99.6) FPR: 0.09% (0.05 - 0.14) 32 16
12/6/19 Detection rate of prenatal screening for Down syndrome has improved over time 120 100 Detection Rate (%) 80 60 40 20 0 5 n n n A n e e 3 e e N > e e e e D r r r r e c c c f c c g s s s s A e d r d e l a e p t u t i s a r Q e T r m g e i r t t n t I s r i F 33 Genomic variation Down syndrome 22q deletion syndrome Cystic fibrosis 34 17
12/6/19 Availability of Genetic Tests Most of these are for inherited disorders 35 36 18
12/6/19 • Estimate the risk of metastatic relapse • Estimate the risk of progression • Monitor the efficacy of treatment • Identify molecular targets 37 38 19
12/6/19 39 40 20
12/6/19 41 Non-Invasive Single Gene Tests • Maternal and fetal cell free DNA cannot be easily distinguished • However, can identify de novo or paternal gene mutation • This includes blood type if mother is Rh negative and fetus is Rh positive 42 21
12/6/19 • N=47 cases • Correct in 46 (96.2%) • Useful tool in 3 rd trimester to distinguish IUGR from achondroplasia Chitty LS, et al. Prenat Diagn 35:656, 2015 43 37 yo G1P0 at 28 wks 44 22
12/6/19 45 46 23
12/6/19 47 • De novo mutations • Many associated with advanced paternal age • No prospective data on performance • Not ready for routine use 48 24
12/6/19 Spectrum of Congenital Disease Chromosomal • Gene Autosomal recessive microarray sequencing Autosomal dominant • Carrier X-linked screening Copy number Chromosomal/ karyotype variants Cell free DNA • • Amniocentesis Structural Malformations Ultrasound 49 Recessive inheritance Affected Unaffected carriers 50 25
12/6/19 Recessive inheritance Affected Unaffected carriers 51 What is the purpose of prenatal carrier screening? 52 26
12/6/19 What is the purpose of newborn screening? 53 Screening for Screening for Affected Carriers NEWBORN PRENATAL Birth s k Conception w 0 2 Carrier Newborn screening screening 54 27
12/6/19 55 Wilson and Junger: Criteria for screening for disease • A good test is available • The disorder is common • The disorder is severe • There is an intervention • Testing is voluntary and patients give informed consent 56 28
12/6/19 History of Prenatal Carrier Screening 1. Hemoglobinopathies 1970’s 2. Tay Sachs disease 1971 3. Canavan disease 1998 4. Cystic fibrosis 2001 5. Familial dysautonomia 2004 6. Spinal muscular atrophy 2008 (ACMG) 7. Spinal muscular atrophy 2017 (ACOG) 8. Expanded Jewish panel 2008 (ACMG) 9. Expanded Jewish panel 2017 (ACOG) 10. Expanded carrier screening 2017 (ACOG) 57 Traditional Carrier Screening • Focus on ancestry and family history • Small number of diseases • High frequency in a certain population • Severe morbidity or mortality • Fetal, neonatal or early childhood onset • Well-defined phenotype Sickle cell disease Tay-Sachs disease 58 29
12/6/19 Expanded (Universal) Carrier Screening 59 Expanded (Universal) Carrier Screening Utilization of new technologies to identify carriers of hundreds of genetic conditions simultaneously 60 30
12/6/19 Is More Better? • What are these additional conditions? • What is the process for adding new conditions? • Is the test accurate? • How often does the test find something? • What happens then? 61 Newborn vs prenatal screening Disorder is important à test is developed and introduced Technology is developed à test is introduced 62 31
12/6/19 What is on expanded panels and how are disorders chosen? Disorders should be: • Severe • Common • Have a well-described natural history and phenotype • Have a high detection rate 63 What criteria are required by laboratories before adding gene variants to panels? 64 32
12/6/19 Achromatopsia • Decreased visual acuity, nystagmus • Increased light sensitivity • Decreased color discrimination • Non-progressive • Does not lead to blindness • No other organ system affected • Should this be on panels? 65 Expanded Carrier Screening: The Wild West 66 33
12/6/19 Gene variants What criteria are required by laboratories before adding variants to panels? Test is available 67 68 34
12/6/19 Optimal criteria for carrier screening: ACMG and ACOG • Good test is available • Detection rate ≥ 70% • Carrier frequency is high • At least 1 in 100 • Exclusions: • Adult onset • Poorly studied • Prevalence unknown • Incomplete penetrance • Mild phenotype 69 • Evaluated commercially available panels • 27% of included disorders meet criteria per ACMG and ACOG 70 35
12/6/19 How Often Do Tests Find Something? 71 What Then? 24-45% will have something • Explain to the patient • Test the partner (he might not have insurance) • He will often have something else • If low detection rate on original panel, do gene sequencing • Explain all this to the patient 72 36
12/6/19 A real patient story • Patient and partner had expanded carrier screening during first pregnancy (in NY) • Both carried a variant for Zellweger disease • Life-threatening metabolic disorder • Usually neonatal death • Had prenatal diagnosis: fetus carrier 73 74 37
12/6/19 Delayed pregnancy for THREE years • Saw GC for pre-conception counseling • Planning for preimplantation genetic testing • GC was having a slow day…. 75 Results 76 38
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