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N O F I N A N C I A L D I S C LO S U R E S OBJECTIVES I recommend - PowerPoint PPT Presentation

Dec 03, 2023 •260 likes •383 views

6/13/2019 N O F I N A N C I A L D I S C LO S U R E S OBJECTIVES I recommend Cell Free DNA for: 41% Background A. All my patients 32% 28% When is it the right test? B. Only for women over age When is it the wrong test? 35

  1. 6/13/2019 N O F I N A N C I A L D I S C LO S U R E S OBJECTIVES I recommend Cell Free DNA for: 41%  Background A. All my patients 32% 28%  When is it the right test? B. Only for women over age  When is it the wrong test? 35  What are some new things it might do? C. For any patient with s t 3 5 n . . e e . t i a g m a u p e r r y v s e m o a l l l n m A m e r o o n w b abnormal serum screening a o r h f t y w i l O n t n e i t p a y n a r F o 1

  2. 6/13/2019 C a s e # 1 : P a t i e n t W N 37-year-old G5P4004 at 12 weeks gestation • What testing options should be -3 healthy children offered? -1 son with Wolf-Hirschorn syndrome - Parental testing performed Father is a carrier of a balanced translocation • 52% A. Cell free DNA ** 25% recurrence risk 43% B. Invasive testing with CVS C. Cell free DNA followed by CVS 5% Cell free DNA Invasive testing with CVS only if abnormal Cell free DNA followed by CVS only if ... C e l l F r e e D N A - cfDNA: Common Clinical wh a t i s i t ? Applications Made up of short • segments of fetal DNA  Aneuploidy (<200 bp)  Sex determination Origin is primarily • placental  Fetal RH status Results from apoptosis • Circulate in maternal • plasma 2

  3. 6/13/2019 Cell Free DNA: Characteristics  cfDNA represents ~10-15% of total DNA in maternal plasma 1  Reliably detected after 7 wks gestation 2  Higher concentrations late in gestation  Short half life (16 min), undetectable by 2 hrs postpartum 3 JAMA. 2018;320(6):591-592. doi:10.1001/jama.2018.9418 Why does the technique matter? T e c h n i q u e s MPSS Targeted SNP • Amplification and • Sequencing of • Comparison of  Massively parallel shotgun sequencing (MPSS) sequencing of all regions of interest SNPs of maternal cfDNA only origin to fetal  Targeted sequencing Benefit: Broad, Benefit: less Benefit: accuracy • • •  Single nucleotide polymorphisms (SNP) analysis looks at cfDNA expensive is equal across from all chromosomes chromosomes May allow • Limitations: Cost, differentiation • requires minimum between triploidy, fetal fraction of uniparental 4% disomy, maternal mosaicism 3

  4. 6/13/2019 Fetal Fraction F e t a l F r a c t i o n Prenatal Diagnosis 2012; 32(13) p 1233-41 Taglauer, WES, Wilkins-Haug L, Bianchi DW Review: cell-free fetal DNA in maternal circulation as an indicatation of placental health and disease Factors that impact fetal fraction Why does fetal fraction matter?  Maternal BMI - increased BMI associated with decreased FF  Failed to provide a result in 20% of women >250 lb and 50% of women >350 lb.  Gestational age The less fetal DNA, the harder to  Increases after 21 weeks tell normal from abnormal  Aneuploidy  Increased FF with infants with T21  Decreased FF with infants with T18  Twins 4

  5. 6/13/2019 Cell free DNA screening: Cell free DNA screening: Biologic Challenges Biologic Challenges False Positives False negatives  Unrecognized or “vanishing”twin  Low level of fetal DNA  Placental Mosaicism  Placental mosaicism  Low level maternal mosaicism, esp. sex  Maternal genetic variation (copy chromosomes number variants)  Maternal Malignancy C F D N A a n d a n e u p l o i d y : Cell free DNA screening: P e r f o r m a n c e o f c f d n a Biologic Challenges Failed Results  Increased BMI  Low level of fetal DNA  Fetal Aneuploidy 5

  6. 6/13/2019 PPV calculator C F D N A a n d a n e u p l o i d y : P e r f o r m a n c e o f c f d n a  It is important to counsel patients about the positive predictive value (PPV) of the test  PPV is influenced by prevalence of a disease  An individual PPV can be calculated using maternal age or risk generated from prior screening test  https://www.perinatalquality.org/vendors/ nsgc/nipt/ Cell Free DNA for Aneuploidy in Cell Free DNA for fetal sex? Twins  Unaffected twin may mask an affected twin  False positive rate is high for monosomy X  Although initial studies are reassuring regarding use of cfDNA for T21 in twins, the overall data  Patients may learn about possible sex are limited chromosome aneuploidy even when they are primarily interested in fetal sex  Not currently recommended by ACOG/SMFM  For higher order multiples  Maternal age and  In some cases, may be abnormal if the nuchal translucency measurement for mother has an undiagnosed sex aneuploidy estimation chromosome aneuploidy 6

  7. 6/13/2019 Cell Free DNA Vs. Serum Cell free DNA for ultrasound screening abnormalities?  What if CF DNA is normal followed by  Negative cfDNA and isolated ‘soft marker’ abnormal serum screening  Diagnostic testing is not recommended solely for this indication  Raises concern for other chromosomal  Structural abnormality on ultrasound abnormality  Offer diagnostic testing using microarray  I n a study by Norton et al. the residual risk was 2%  The majority of congenital structural abnormalities are due to microdeletions or single gene disorders  The lowest detection rate for cfDNA in that cannot reliably be detected by cell free DNA women who were <25 years old  Invasive testing is recommended Cell free DNA for Rh blood Cell Free DNA for typing? Microdeletions?  Chromosomal microdeletions account for many syndromes  Lo and colleagues accurately assess fetal  May have developmental delay and medical issues Rh status using cfDNA using PCR  There are approximately 40 well described microdeletions  Negative predictive value as high as 98%  Low baseline prevalence of each microdeletion syndrome PPV is signficantly impacted   Moise and colleagues (2016) reported false negative in 1 in 520 cases and inconclusive results in 5-6% of cases 7

  8. 6/13/2019 Microdeletions are More Common Microdeletions are rare Than Down Syndrome for Women Under 40 Adapted from: Snijders, et al. Ultrasound Obstet Gynecol 1999;13:167–170 S h o u l d a l l w o m e n b e Microdeletions can be o f f e r e d s c r e e n i n g f o r m i c r o d e l e t i o n s ? detected by cfDNA, but….  Difficult to validate  Low positive predictive value  In a recent study, investigators examined 8141 single pregnancies with NIPT  51 positive cases for chromosomal microdeletions or microduplications  only 13 (36%) true-positive cases 8

  9. 6/13/2019 Prevalence of many microdeletion syndromes is Back to case #1… unknown  Our patient underwent cell free DNA testing with  May be caused by different molecular mechanisms micro deletions  Smaller deletions more difficult to detect  Her results were normal so she declined any further testing  22q syndrome (~1/4000)  Level II ultrasound was notable for unilateral cleft  85% have 3Mb deletion , 15% smaller lip and palate and abnormal profile  “97% detection” refers to only 3Mb deletion  Amniocentesis confirmed deletion of 8.9 MB deletion on 4p consistent with Wolf-Hirshorn C e l l f r e e D N A t e s t i n g f o r s i n g l e g e n e d i s o r d e r s Disorders that are a result of DNA changes in a single gene  May affect up to 1% of all pregnancies  Requires identifying fetal DNA that is unique from maternal  Current clinically available for limited conditions   Screening for these microdeletions has not been validated Achondroplasia  in clinical studies. Thanatophoric dysplasia  Apert syndrome  Cystic fibrosis   Routine cell-free DNA screening for microdeletion syndromes should not be performed. 9

  10. 6/13/2019 T h e F u t u r e : N o n I s m o r e i n v a s i v e a l w a y s W h o l e b e t t e r ? G e n o m e • OBTAI N INFORMATION ABOUT THE ENTI RE S e q u e n c i n FETAL GENOME g • Coding and non coding • RAI SES BOTH portions PRACTI CAL AND ETHICAL I SSUES • Single nucleotide variants • MAY GIVE • Deletions and Duplications I NFORMATI ON REGARDI NG RISK FOR • Copy number variants ADULT ONSET CONDITI ONS THAT ARE NOT RELEVANT Current guidelines ACOG/SMFM guidelines  Conventional screening is most appropriate first line screen for most patients  Ethically any patient may choose cfDNA screening, but should be counseled regarding limitations and benefits  Diagnostic testing is required to confirm abnormal results before irreversible decisions  Not recommended in twin pregnancies  Microdeletion/expanded panels for cell free DNA are not recommended 10

  11. 6/13/2019 What do we do at UCSF? Thank you!  Serum integrated screening  First trimester screening with Nuchal Translucency  Screen positive patients are counseled to undergo invasive testing  If a patient declines invasive testing, cell free DNA is offered as an option that is paid for by California in this setting  We do occasionally recommend cell free DNA for specific single gene disorders Thank you!  Concern for achondroplasia  RH disease 11

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