10/17/2019 UPDATE ON PERINATAL Disclosure GENETICS o Research support: Natera o Consultant, Scientific Advisory Board: Invitae Mary E. Norton MD Professor, Obstetrics, Gynecology, and Reproductive Sciences University of California, San Francisco 2019 UCSF Obstetrics and Gynecology Update 1 2 Gartner Hype Cycle Genomic variation Down syndrome Cell free DNA screening 22q deletion syndrome Chromosomal microarray Exome sequencing Cystic fibrosis 3 4 1
10/17/2019 The Prenatal Testing Paradigm Detection rate of prenatal screening for Down syndrome has improved over time Down syndrome 120 100 Detection Rate (%) Yes No 80 60 40 Terminate pregnancy 20 0 No Yes 5 6 Analysis of cell free DNA 1997 7 8 2
10/17/2019 cfDNA screening for T21: meta-analysis ( Gil et al, Ultrasound Obstet Gynecol, 2017) High Risk, Low Risk, and Positive Predictive Value Detection Rate: 99.7% False Positive Rate: 1/2500 DR: 99.2% (98.5 - 99.6) FPR: 0.09% (0.05 - 0.14) 9 10 Wang et al, Genetics in Medicine, 2014 Aneuploidy No. of positives No (%) confirmed T21 41 38/41 (93%) T18 25 16/25 (64%) T13 16 7/16 (44%) 45,X 16 6/16 (38%) Total 98 67 (67%) 11 12 3
10/17/2019 PPV Calculator: www.perinatalquality.org Risk Group Positive predictive value Entire cohort 81% (mean age 30.7 yrs Maternal age <35 yo 76% Low risk serum FTS (<1/270) 50% 13 14 15 16 4
10/17/2019 DOWN SYNDROME!! 17 18 Spectrum of Congenital Disease “How did this happen? I had the non-invasive Conditions • 1/300 amnio…” Autosomal recessive found by pregnancies Autosomal dominant microarray • 20% of X-linked infant deaths Copy number Chromosomal/ karyotype variants Half of these are Down syndrome Structural Malformations 19 20 5
10/17/2019 Spectrum of Congenital Disease Chromosomal microarray Chromosomal • Gene o “Lab-on-a-chip” Autosomal recessive microarray sequencing Autosomal dominant o Tests for thousands • Carrier X-linked screening of copy number Copy number Chromosomal/ variants at the karyotype variants same time • Cell free DNA o Microdeletions and • Karyotype Structural microduplications Malformations Ultrasound 21 22 Microdeletions are genomic imbalances Russell Silver syndrome: Small, asymmetric detected by microarray but not karyotype Mild learning disabilities Ch 7 Prader- Willi : Hypotonia, Ch 15 significant learning disabilities, obesity Angelman Some Microdeletion syndrome : Syndromes Severe intellectual disability and speech impairment Ch 5 Cri du chat syndrome : Poor feeding and growth, microcephaly, severe learning difficulties Miller et al, 2010, AJHG 23 24 6
10/17/2019 Chromosomal Microarray (CMA) Rate of abnormalities by maternal age for Prenatal Diagnosis (Microarray abnormalities) 35 yo Indication for Testing Clinically Relevant (N=96) U/S Anomaly ( N=755) 6.0% AMA ( N=1,966) 1.7% Positive Screen ( N=729) 1.7% Other ( N=372) 1.3% Increasing maternal age 25 26 Microdeletion syndromes tested by cfDNA expanded panels Cell free DNA: Expanded panels Syndrome Frequency Features 22q11.2 1/4,000 Varies: cardiac, palatal, immune, o Trisomies 9, 16 and 22 (DiGeorge) intellectual disability • Rarely seen in viable pregnancies except as mosaics 1q36 1/10,000 Severe intellectual disability (ID), +/- • Common causes of confined placental mosaicism obvious structural anomalies - Much more common in CVS samples than amniocentesis • Even complete trisomy in the placenta often Angelman 1/20,000 Severe ID, seizures, speech delay associated with a normal fetus Prader-Willi 1/30,000 Obesity, ID, behavioral problems o Selected microdeletions • 22q, 1q36, 5p-, 4p-, 15q11-13 Cri-du-chat 1/50,000 Microcephaly, ID, +/- CHD • Also 8q-, 11q- Wolf-Hirshhorn 1/50,000 ID, seizures, +/- CL/CP o MaterniTGenome Total 1/2500 27 28 7
10/17/2019 Diagnostic confirmation for cfDNA Chromosomal microarray vs cfDNA: for microdeletions Bottom line Deletion Total # of # Positive Predictive cases confirmed Value o Diagnostic testing with chromosomal 1p 21 1 4.8% microarray is the best test for pregnant women who want as much information as 4p 6 1 16.7% possible about their fetus. 5p 45 6 13.3% o Women should be counseled about the chance 15q 80 5 6.3% of finding a variant of uncertain significance 22q 183 12 6.6% o Cell free DNA can detect only a tiny number of Total 335 25 7.4% the total microdeletions Schwartz et al, Prenatal Diagn, 2018 29 30 MaterniTGenome: “Non-invasive Genome” Screen positive rate: 5.4% December, 2017 31 32 8
10/17/2019 Cell free DNA and cancer 33 34 35 36 9
10/17/2019 Spectrum of Congenital Disease Traditional screening cfDNA screening Chromosomal Trisomy 18, 21, +/-13 Trisomy 13, 18, 21 • Gene Autosomal recessive microarray sequencing Spina bifida and ventral Sex chromosomes Autosomal dominant • Carrier wall defects (MSAFP) X-linked +/- microdeletions screening Other chromosomal Maternal cancer Copy number Chromosomal/ Early dx fetal anomalies, karyotype variants Maternal CNV including cardiac (NT) • Cell free DNA Maternal sex Adverse obstetric • Amniocentesis chromosomal Structural outcomes aneuploidy Malformations Preeclampsia, PTB, FGR Ultrasound 37 38 Screening for Screening for History of Prenatal Carrier Screening Affected Carriers 1. Hemoglobinopathies 1970’s NEWBORN PRENATAL 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) Carrier Newborn screening screening 39 40 10
10/17/2019 Expanded (Universal) Carrier Screening Expanded (Universal) Carrier Screening Utilization of new technologies to identify carriers of multiple genetic conditions simultaneously 41 42 The future: Whole genome sequencing The future: Whole genome sequencing 43 44 11
10/17/2019 Separating the Wheat from the Chaff Whole Genome and Exome Sequencing o Whole Genome Sequencing • Obtaining the complete sequence of all 3 billion base pairs of DNA in any individual o Exome Sequencing • Obtaining the complete sequence of the ~2% of the genome containing the exons that encode proteins 45 46 “The Thousand Dollar Genome” What is a “normal” genome? “The Ten Thousand Dollar Interpretation” 47 48 12
10/17/2019 What is exome sequencing? A genome is like watching the An exome is like game from beginning to end reading the highlights exome sequencing is a technique for sequencing all of the protein-coding genes in a genome (known as the exome ). 49 50 Clinical Sequencing Evidence Generating Exome sequencing in fetal anomalies Research Consortium: Is There Clinical Benefit? Institution Study focus Baylor Pediatric cancer Hudson Alpha Sequencing newborns N=234 10% diagnostic yield Kaiser Cancer predisposition Lancet 2019 Mt Sinai Pediatric undiagnosed disorders UCSF Pediatric and prenatal disorders UNC Adult and pediatric disorders UW Coordinating center N=596 8.5% diagnostic yield 51 52 13
10/17/2019 41 y.o. G1P0 at 32 weeks gestation Prenatal WES Results 70 10/63 = 16% 63 60 5/10 (50%) nonimmune hydrops 50 48 40 30 20 10 6 4 3 3 2 0 Definitive Positive Probable Positive Inconclusive Investigational Negative Secondary Findings Total Results Findings Returned 53 54 Fetal evaluation Fetal MRI o Normal microarray o Meta-genomic analysis: no pathogens identified Markedly abnormal o Whole exome sequencing: o Global cerebral volume loss • De novo heterozygous missense variant in TUBB2A o Markedly diminished white matter volume • TUBB2A gene encodes beta tubulin, a subunit of and germinolytic cysts in the ganglionic microtubules. eminences • Variants in this gene are associated with complex o Appearance destructive: patient ID specialist cortical dysplasia with other brain malformations (MIM#615763), an emerging autosomal dominant syndrome characterized by seizures, brain abnormalities and developmental delay 55 56 14
10/17/2019 Prenatal whole exome sequencing o Broad range of diagnostic yield: 6.2-80% • Inclusion criteria • Analysis of trios o Limited genotype–phenotype correlation for genetic disorders identified in the fetal period • Ultrasound imaging is limited • Fetal phenotypes of many conditions are not well described • Some disorders likely perinatal lethal o Need improved pipelines for prenatal sequencing 57 58 What is the future? Conclusions o 3 million women undergo prenatal genetic testing each year o Genetic testing can identify far more than Down syndrome o There are many reasons for undergoing prenatal testing beyond pregnancy termination o Rapid uptake of cfDNA screening suggests that women will continue to desire the next best prenatal genetic test o The question is not whether prenatal noninvasive genome sequencing should be performed, but how to optimally implement 59 60 15
10/17/2019 Thank you! 61 16
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