Prenatal Ultrasound Interpretation and Genetic Testing ... · •Fetal imaging with ultrasound...
Transcript of Prenatal Ultrasound Interpretation and Genetic Testing ... · •Fetal imaging with ultrasound...
11/2/2018
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Prenatal Ultrasound
Interpretation and
Genetic Testing
WorkshopNovember 1st, 2018
Esther Friedrich, MDSouthern California Permanente Medical
Group
Department of Obstetrics & Gynecology
Maternal Fetal Medicine & Genetics
Esther Friedrich, MD – November 2018 – Interregional Symposium
Disclosures
• NONE
Esther Friedrich, MD – November 2018 – Interregional Symposium
Objectives
▪ Understand the genetic basis and evolution of
current genetic screening and testing methods
commonly used in OB & Gyn including obstetric ultrasound
▪ Be able to counsel particularly obstetric patients
accurately about their choices of genetic
screening and testing before, during and after pregnancy
▪ Learn about newly developing methods of
genetic screening and testing applicable to an
OB & Gyn population
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Esther Friedrich, MD – November 2018 – Interregional Symposium
On May 21, 2014, The American Board of Medical Genetics changed its name to the
American Board of Medical Genetics andGenomics [ABMGG]
In 2011, The American College of Medical
Genetics changed its name to American College of Medical Genetics and Genomics
[ACMG]
Background
Esther Friedrich, MD – November 2018 – Interregional Symposium
Genetics:The study of heredity and the variation of
inherited characteristics
ge·net·ics [/jəˈnediks/]
Genomics:
The branch of molecular biology concerned with the structure, function, evolution and
mapping of genomes
ge·no·mics [/jēˈnōmiks,-ˈnäm-/]
Definition
Esther Friedrich, MD – November 2018 – Interregional Symposium
▪ 1/30 (3-4%) of all neonates have clinically significant recognized anomaly
▪ 1/12 (5-8%) of children recognized to have a clinically significant anomaly by age 5
▪ Each of us carry 5 – 10 abnormal recessive genes
▪ Up to 50%+ of birth defects/mental
retardation have genetic basis
Background
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Overview
• Diagnosis vs Screening
• Genetic Basics,Terminology & Disease
• Genetic Counseling
• Prenatal Screening & Diagnosis– Serum Screening and Blood tests
– Genetic Ultrasound
– Invasive Diagnosis
– Preconception
• Future direction
Esther Friedrich, MD – November 2018 – Interregional Symposium
Overview
• Diagnosis vs Screening
• Genetic Basics,Terminology & Disease
• Genetic Counseling
• Prenatal Screening & Diagnosis– Serum Screening and Blood tests
– Genetic Ultrasound
– Invasive Diagnosis
– Preconception
• Future direction
Esther Friedrich, MD – November 2018 – Interregional Symposium
Screening vs. diagnostic
testing
Relevant
Populations
Type of
Assessment
Type of Test
Entire Population(e.g., all people should
have their cholesterol
checked every two
years)
At-risk(e.g., a cardiac
stress
test to evaluate
heart damage)
Risk Assessment(e.g., you are at a higher
risk for cancer)
Definitive Answer(e.g., you have cancer)
ScreeningDiagnostic
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Esther Friedrich, MD – November 2018 – Interregional Symposium
• Genetic testing:Utilizing specific assay or DNA test to evaluate genetic status of individual at high risk for particular inherited condition
• Genetic screening:Utilizing various genetic tests to evaluate populations or groups of individuals independent of family history or clinical symptoms
Screening vs. diagnostic
testing
Esther Friedrich, MD – November 2018 – Interregional Symposium
Genetic Screening
• DNA testing – E.g. Cystic Fibrosis
• Chromosome Analysis
• Evaluating a gene product– E.g. thyroid hormones, hemoglobin
• Measuring a metabolite– E.g. PKU, Tay Sachs
• Fetal imaging with ultrasound
• Serum screening and variants
Esther Friedrich, MD – November 2018 – Interregional Symposium
Overview
• Diagnosis vs Screening
• Genetic Basics,Terminology & Disease
• Genetic Counseling
• Prenatal Screening & Diagnosis– Serum Screening and Blood tests
– Genetic Ultrasound
– Invasive Diagnosis
– Preconception
• Future direction
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Basic Molecular &
Cytogenetics
• Chromosome
– Strand of DNA, divided
into two arms by a
centromere
– Normal human cells
have 46 (23 pairs)
• Short arm – p
• Long arm – q
Esther Friedrich, MD – November 2018 – Interregional Symposium
• Karyotype
– Chromosomal constitution of an individual
Basic Molecular &
Cytogenetics
Liken to “books” containing recipes
Contain coding and
non-coding regions (“ads”)
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• Non-disjunction
• Robertsonian translocation
• Reciprocal translocation
• Deletion/Duplication
• Insertion
Basic Molecular &
Cytogenetics
Basic Chromosomal Errors
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Esther Friedrich, MD – November 2018 – Interregional Symposium
• DNA - Genes• contains within it the information of all aspects of embryogenesis,
development, growth, metabolism and reproduction
• each cell: full genome• ~25,000 genes encode proteins
• ~2 meters of DNA coiled in
nucleus
• 4 base pairs = 6 billion nucleotides
Basic Molecular &
Cytogenetics
Esther Friedrich, MD – November 2018 – Interregional Symposium
FISH
• FISH
– Fluorescence in situ hybridization
– Probes specific to chromosome or gene locus; can find specified areas, e.g. microdeletion DiGeorge
Esther Friedrich, MD – November 2018 – Interregional Symposium
FISH
FISH
Used for whole chromosome paint probes (marker), as unique sequence probes or to perform subtelomericanalysis
FISH can find the “recipes” in a book
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Basic Genetics
Microdeletion syndromes
• 22q11.2 deletion
[DiGeorge, VCFS etc]
• 17p11.2 deletion [Smith-
Magenis]
• 15q11-q13 deletion [Prader-Willi, Angelman]
• 7q11.23 deletion [Williams]
Deletions of < 3-5Mb, not usually seen on microscopy
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Basic Genetics
Uniparental disomy
• individual has two copies
of allele but both come
from one parent
– Loss of maternal allele –
Angelman
– Loss of paternal allele –
Prader Willi
– Known clinically
significant on
chromosomes 6, 7, 11, 14, 15
• If gene is imprinted,
normal development
requires presence of both maternally and
paternally derived gene copy
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Array CGH
[Comparative genomic hybridization]
• Chip = FISH x thousands
• tests for thousands of genes
at the same time
• No culture (uses DNA)
Patient DNA is compared to normal reference DNA on glass
slide
Fluorescent tags are use to
hybridize to specific regions, read by laser scanners
But: also identifies benign changes
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Esther Friedrich, MD – November 2018 – Interregional Symposium
• Green = added material
= duplication
• Red = deleted
material = deletion
• Yellow = c/w
reference DNA
= no change in CNVs
(copy number variants)
• Balanced translocations
cannot be detected!
• Finds chunks of pages
extra or missing
in all books!
Genetic Microarray
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Genetic Microarray
Different types of probes commonly utilized:
BAC clones: 0.5-1 Mb
detection
Oligo-array: 50-500 Kb
detection
SNP-array: 3-10 Kb
If a new change is identified, parental blood is obtained to
identify the change as
significant, the majority are benign polymorphisms
Targeted vs Whole Genome
Esther Friedrich, MD – November 2018 – Interregional Symposium
Genetic Microarray - SNP
SNP’s are single nucleotide polymorphisms, the smallest detectable
changes. Graduated to clinical use.
Medi-Cal approved use of micro-array
analysis 2009
Detects ~ 5-20% genetic causes in previously unexplained MR
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Basic Genetics
Single Gene Disorders
• Result of mutations in genes in the nuclear genome
• Usually follow mendelian inheritance
• Listed in OMIM
• > 3917 diseases logged
• E.g. NF1, DMD (2.2Mb)
• Different mutations in the
same gene can cause
different disease
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DNA Sequencing
Method of determining the nucleotide sequence of adenine, guanine,
thymine and cytosine within a gene
Today sequencing is an automated
process
Detects mutations on a single nucleotide base
Detects “spelling errors”
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Basic Genetics
Inheritance patterns
• Autosomal dominant – e.g. Achondroplasia,
Marfan’s
• Autosomal recessive – e.g. CF, sickle cell
• X-linked recessive – e.g. Duchenne Muscular
Dystrophy
• X-linked dominant – e.g. incontinentia pigmenti
• Multifactorial inheritance – e.g. NTD’s, heart defects, cleft lip/palate, DM, autism
• Mitochondiral inheritance – e.g. Myoclonic epilepsy
with ragged red fibers (MERRF)
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Overview
• Diagnosis vs Screening
• Genetic Basics,Terminology & Disease
• Genetic Counseling
• Prenatal Screening & Diagnosis– Serum Screening and Blood tests
– Genetic Ultrasound
– Invasive Diagnosis
– Preconception
• Future direction
Esther Friedrich, MD – November 2018 – Interregional Symposium
Genetic Counseling
Providing individuals with information on nature, inheritance and implications of genetic disorders to enable them to make informed medical and personal decisions
Organized initially as a subgroup in the ASHG, now individually active
Masters training programs throughout the US, board certification through ABGC/ABMG.
Esther Friedrich, MD – November 2018 – Interregional Symposium
Genetic Counseling
- Indications
• Previous affected child
• Family history of hereditary condition or birth defect
• Advanced maternal age or positive screening
• Consanguinity
• Ethnicity associated with increased risk
• Infertility, recurrent miscarriage
• Maternal disease
• Known carrier of genetic disease
• Fetal anomaly on ultrasound
• Positive newborn screening
• Familial cancer syndrome
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Who to Refer to Genetics
(counseling vs clinical)
• Ultrasound abnormalities (excluding single
soft sign)
• California Prenatal Screen positive results
• Family history of a possible genetic condition
• Prior pregnancy with a chromosome
condition
• Carrier of a genetic condition
• Members who are interested in
CVS/amniocentesis
• Members with more extensive questions
Esther Friedrich, MD – November 2018 – Interregional Symposium
Overview
• Diagnosis vs Screening
• Genetic Basics,Terminology & Disease
• Genetic Counseling
• Prenatal Screening & Diagnosis– Serum Screening and Blood tests
– Genetic Ultrasound
– Invasive Diagnosis
– Preconception
• Future direction
Esther Friedrich, MD – November 2018 – Interregional Symposium
Overview
• Diagnosis vs Screening
• Genetic Basics,Terminology & Disease
• Genetic Counseling
• Prenatal Screening & Diagnosis– Serum Screening and Blood tests
– Genetic Ultrasound
– Invasive Diagnosis
– Preconception
• Future direction
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Prenatal Diagnosis
• Serum Screening – California Prenatal Screening Program
• Non-Invasive Prenatal Screening
• Other important Blood tests
• Genetic Ultrasound– First Trimester
– Second Trimester
– Prenatal Dysmorphology, MRI, 3D and 4D US
• Invasive Diagnosis– Amnio, CVS, PUBS
– Karyotyping, FISH, PGD
– Single Genes
– Metabolic Disease
– Microarray, Gene Sequencing
Esther Friedrich, MD – November 2018 – Interregional Symposium
Who should be offered prenatal screening and diagnostic testing?
➢ Screening:➢ All patients: offer screening through the
California Prenatal Screening Program (CPSP).➢ Advanced maternal age patients: also offer
Non Invasive Prenatal Testing (NIPT).
➢ Diagnostic testing (CVS or amniocentesis):
➢ AMA patients➢ Patients whose fetus is at risk for conditions that
can be diagnosed through these procedures (e.g., cystic fibrosis, Tay Sachs, Sickle Cell
disease)
➢ All patients
Esther Friedrich, MD – November 2018 – Interregional Symposium
Aneuploidy Screening
• What it USED TO BE:
• State of California expanded
AFP program – Quad screening• What
– Maternal serum alpha feto protein (MSAFP)
– Human chorionic gonatotropin (hCG)
– Unconjugated estriol (uE3)
– Inhibin –A (Inh)
• When
– 15 – 20 (22) weeks, most accurate at 16 – 18
weeks
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• What it IS NOW:
• State of California Prenatal
Screening Program (CPSP)• What
– Quad marker screening
– Serum Integrated Screening
(combines 1st & 2nd trimester blood results)
– Sequential Integrated Screening
(combines NT, 1st & 2nd trimester blood results)
- NIPT & 2nd trimester blood results
• When: 10 – 20 (24) weeks of gestation
Aneuploidy Screening
Esther Friedrich, MD – November 2018 – Interregional Symposium
CA Prenatal Screening
What it IS NOW:
First trimester blood
10 0/7 – 13 6/7 wks
PAPP-A
hCG
Nuchal translucency (11 2/7 – 14 2/7)
If CVS or NIPT done, serum screening for NTD
and SLOS only in the second trimester.
State covers both blood, US and follow up studies – unless
NIPT done outside of CPSP - NEW 11/2013
Sign Consent or Decline.
Esther Friedrich, MD – November 2018 – Interregional Symposium
• State of California Prenatal Screening
Program – it still screens for:– Neural tube/abdomen wall defects
– Trisomy 21
– Trisomy 18 (risk not assessed for twins)
– SLOS – Smith-Lemli-Opitz Syndrome
– SCD = SLOS, Congenital anomalies and fetal demise
Autosomal recessive, incidence 1 : 60,000-100,000
Defect in cholesterol metabolism (7DHC is increased)
Microcephaly, cleft lip, MR, dysmorphic features
Aneuploidy Screening
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Down syndrome detection rates for
various screening tests
• Maternal age ≥ 35 at delivery ~20% [2% PPV]
• Midtrimester triple screen overall 60% [2% PPV]
– Maternal age < 35 50%
– Maternal age ≥ 35 70%
• Midtrimester quad screen 80% [2% PPV]
• Midtrimester “genetic ultrasound” 25-85%
• First trimester screen 80-85% [3% PPV]
• Serum Integrated screen 80%
• Sequential Integrated screen ~90% [5% PPV]
• NIPT ~99% [60-90% PPV]
Malone, 2005; Cuckle 2008 - FASTER
Esther Friedrich, MD – November 2018 – Interregional Symposium
Prenatal Diagnosis
• Serum Screening – California Prenatal Screening Program
• Non-Invasive Prenatal Screening
• Other important Blood tests
• Genetic Ultrasound– First Trimester
– Second Trimester
– Prenatal Dysmorphology, MRI, 3D and 4D US
• Invasive Diagnosis– Amnio, CVS, PUBS
– Karyotyping, FISH, PGD
– Single Genes
– Metabolic Disease
– Microarray, Gene Sequencing
Esther Friedrich, MD – November 2018 – Interregional Symposium
NIPT is a Quantitative Analysis
Image taken from Illumina website: Patient Counseling Guide for Reproductive Genetics
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Non-invasive prenatal
diagnosis
• Fetal Rh determination
• Fetal sex determination
• Fetal aneuploidy detection
• Targeted fetal mutation analysis?
Genet Med. 2013 May;15(5):395-8. doi: 10.1038/gim.2013.29. Epub 2013 Apr 4.
ACMG statement on noninvasive prenatal screening for fetal aneuploidy.
ACOG Committee Opinion # 545, December 2012:
“Noninvasive Prenatal Testing for Fetal Aneuploidy”
Esther Friedrich, MD – November 2018 – Interregional Symposium
Non-invasive prenatal
diagnosis
Esther Friedrich, MD – November 2018 – Interregional Symposium
NIPS/NIPT
• Pursued for > 4 decades
• Desai and Cregel showed 1963:
• Cells pass between mother and fetus
• Fetal cells can be extracted, quantified,
molecularly analyzed
• Presence of fetal DNA in maternal plasma and serum
• Lo, YM et al 1997 Lancet, 350:845-7
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• ffDNA/ffRNA results from placental apoptosis
• Present in early gestation ~5-7 wks GA
• Cleared within hours of placental removal
• Shows specificity for placental gene
expression
• Levels are altered by GA, BMI, aneuploidy
• Levels are not altered by race, parity, smoking, age, mode of conception,
placental volume
• Fetal genes distinguished as different by SRY presence, paternal genes
NIPS/NIPT
Esther Friedrich, MD – November 2018 – Interregional Symposium
Possible by next generation sequencing
Massively parallel genomic sequencing
Identifier codes
added for
multiplexing (12-96)
10s of millions DNA
fragments sequenced at
the same time
First 36 bases are
sequencedRossa W. K. Chiu, 20458–20463, doi: 10.1073/pnas.0810641105
NIPS/NIPT
Esther Friedrich, MD – November 2018 – Interregional Symposium
Each chromosome holds a reference % of genome
Chromosome 1
~8.5% genome
Chromosome 18
~2.8%
Chromosome 21 ~1.3%
Z score represents
sample standard deviations from
the reference%
Rossa W. K. Chiu, 20458–20463, doi: 10.1073/pnas.0810641105
NIPS/NIPT
Massively parallel genomic sequencing
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A Quick Statistics Review
• False Positive = The screening test is positive, but the
baby does NOT have the condition
• True Positive = The test is screen positive, and the baby HAS the condition.
Positive Predictive Value (PPV) = IF a result is screen positive, how often is it a TRUE positive?
Esther Friedrich, MD – November 2018 – Interregional Symposium
A Quick Statistics Review
• Sensitivity = Ability of
a test to correctly identify those with
the disease [true
positive rate]
• Specificity = Ability of a test to correctly
identify those without the disease
[true negative rate]
Esther Friedrich, MD – November 2018 – Interregional Symposium
Sensitivity Specificity
Chiu, BMJ,
2011
824 women
(86 trisomy
21)
2 plex
8 plex
100%
79.1%
97.9%
98.9%
Ehrich,
AJOG, 2011
449 women
(39 trisomy
21)
4 plex 100% 99.7%
Palomaki,
Gen in Med,
2011
1471 women
(212 trisomy
21)
4 plex 98.6% 99.8%
NIPS/NIPT
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MELISSA study (Maternal Blood is Source to Accurately
Diagnose Fetal Aneuploidy)
2,882 women at 60 U.S sites
Prospective, blinded study
All abnormal karyotypes and random euploidkaryotypes
Known karyotype and MPS results were compared
Bianchi et al Obstet Gynecol. 2012 May;119(5):890-901
NIPS/NIPT
Esther Friedrich, MD – November 2018 – Interregional Symposium
Sensitivity Specificity
Bianchi, OB-Gyn,
2012
2,882 women
89 T21
36 T18
14 T13
16 Mononsomy X
100%
97.2%
78.6%
93.8%
100% (CI 98.5-100)
100*
100*
99.8%
Palomaki,
Genetics in Med,
2012
1,971 women
212 T21
59 T18
12 T13
All three (21, 18,
13)
98.6%
100%
98.2%
98.9%
99.8%
99/7%
99.0%
99.9%
* No false positives for autosomal aneuploidies
NIPS/NIPT
Esther Friedrich, MD – November 2018 – Interregional Symposium
Test clinically marketed as “advanced prenatal
screening”:
• screens for T21, 18, 13, X, Y
• still validated ONLY in a high risk population, no multiples:
• AMA > age 35 at time of delivery
• positive prenatal screening
• US anomalies
• prior affected pregnancy
NIPS/NIPT
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Esther Friedrich, MD – November 2018 – Interregional Symposium
NIPS/NIPT
Esther Friedrich, MD – November 2018 – Interregional Symposium
Company Detection Rate (%)
T21 T18 T13
False Positive
Rate (%)
Failure Rate (%)1
Sequenom 99% 99% 92% 0.2-1.3% 0.9%
Verinata >99% 97% 87% 0.1-0.4% <3%
Ariosa >99% 98% 80% unreported 1%
Natera >99% >99% >99% <0.1% 2.9%
1Failed; uninformative; “no call” (e.g., low fetal fraction,
failed QC, failed sequencing)
J Canick, Prenat Diag 2013 Jul;33(7):667-74
NIPS/NIPT
Esther Friedrich, MD – November 2018 – Interregional Symposium
Combined 1st
Trimester
Sequential
Screening
cfFetal DNA
Detection of T21
(>35 y/o)
92% 92% >99%
Timing 1st trimester 1st & 2nd
trimester
1st trimester
Complexity Coordinated
US & blood
Coordinated
US & blood x 2
Blood
Screen positive 22% 4% <1%
PPV 3% 5% 60-90%
NIPS/NIPT
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Esther Friedrich, MD – November 2018 – Interregional Symposium
• Can ffDNA analysis be used in ALL women?
• ffDNA concentration independent of age
• Technology not altered by maternal age
• Sensitivities/Specificities same, PPV will
change
• Estimates:
• High risk population: 50-90%
• All risk population: 20-60%
• Still improved over 2-4% PPV of serum screening
NIPS/NIPT
Esther Friedrich, MD – November 2018 – Interregional Symposium
Screen
positive
Sensitivity Specificity PPV
NIPT 0.68% 100%
(11/11)
99.4%
(172/173)
91.67%
Triple
Screen
14% 54.5%
(6/11)
85%
(148/173)
2.4%
2000 women – NIPT vs triple marker screening
20-34 years old
N = 1916 women in China, 1741 samples analyzed
Song Y et al Prenat Diagn. 2013 Jul;33(7):700-6
NIPS/NIPT
Esther Friedrich, MD – November 2018 – Interregional Symposium
Screen
positive
Sensitivity Specificity PPV
NIPT 0.3% T21
0.2% T18
100%
(8/8)
99.7% 45.5%T21
40% T18
Serum
Screen
(1st or 2nd)
3.6% T21
0.6% T18100%
(8/8)96.4% 4.2% T21
8.3% T18
Almost 2000 women – NIPT vs serum marker
screening
All risk population, average age 29.6 years old
N = 1914 women, CARE study group
Bianchi et al N Engl J Med. 2014 Feb 27;370(9):799-808
NIPS/NIPT
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Prenatal Screening Options and
Detection Rates
NIPT STATE
Timing 10-24 weeks 10-20 weeks
Specimen Maternal Blood Maternal Blood
Risk to Fetus None None
Trisomy 21 99% 80-90%
Trisomy 18 97% 67-81%
Trisomy 13 87% Not Targeted
Sex Chromosome
Abnormalities
90-93% Not Targeted
NTD/AWD Not screened. Screened for
by fetal anatomy ultrasound
or MSAFP
80% NTD/85%AWD
Esther Friedrich, MD – November 2018 – Interregional Symposium
How can false positives be explained?
• Other sources of chromosome specific cfDNA
• Placenta [CPM], multiple reports of discordance for T13, 18 (Futch, 2012, Hall 2013, Pan 2013)
• Vanishing twin, multiple reports of discordance for T13 (Futch 2013; McAdoo 2013 –
ASHG)
• Maternal
• chaotic results – cancer (Osborne, 2013)
• 45,X0 mosaicism, 47,XXX (Nicolaides, 2013; Lau,
2013; Wang, 2014)
NIPS/NIPT
Esther Friedrich, MD – November 2018 – Interregional Symposium
How can false negatives be explained?
• Low fetal fraction
• High BMI
• Dilutional effect
• Increased maternal inflammation(Palomaki, 2011; Canick, 2013; Lapiere, 2013)
• Mosaicism in surviving T13 & T18 pregnancies (Pergament, 2014)
NIPS/NIPT
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NIPT results
• Possible NIPT results:
– NIPT results can also be reported as:
– Aneuploidy Detected
– Aneuploidy Suspected
– No Aneuploidy Detected
– No result
• NIPT does not have 100% accuracy
• Diagnostic testing recommended for
Aneuploidy Detected or Aneuploidy suspected results
– Amniocentesis or CVS are offered
Esther Friedrich, MD – November 2018 – Interregional Symposium
No Screening is Perfect
Neither screening test detects
– Single gene disorders (e.g. cystic fibrosis,
SMA)
– Multifactorial conditions (e.g. diabetes,
bipolar)
– Unknown etiology conditions (e.g. autism, SIDS)
– Physical abnormalities (e.g. cardiac, limb, etc.)
Esther Friedrich, MD – November 2018 – Interregional Symposium
Common Question #1
Patient: “If my NIPT is normal, will my baby be born healthy?”
Provider: “A normal NIPT result is good news. It’s not one-hundred percent and doesn’t look for
everything, but the chance for some common conditions like Down syndrome becomes much
lower.”
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Common Question #2
Patient: “If my NIPT comes back abnormal do I have
to do a CVS or amniocentesis?”
Provider: “No, you don’t have to. If your NIPT comes back abnormal it is VERY IMPORTANT that you have a
consultation with a genetic counselor to discuss your
results in detail and find out what other tests can be done that you are comfortable with. It is important to
remember---never make a decision about your
pregnancy based on the NIPT test result alone—it is a screening test, not diagnostic.”
Esther Friedrich, MD – November 2018 – Interregional Symposium
Common question #3
Patient: “I want the test that will tell me if it’s a
boy or girl…”
Provider: “This test is a screening test for Trisomy
21, 13, 18 and sex chromosome abnormalities.
The purpose of the test is not to tell you the sex of the baby, you will get that information if you
want it. However, it’s not 100% accurate.”
Esther Friedrich, MD – November 2018 – Interregional Symposium
Common Question #4
Patient: “My friend had NIPT and she said it is better than the State blood test. I want that
test.”
Provider: “Let’s see, you will be 30 years old at
delivery, at your age you are considered to
have a low risk for chromosome problems. At Kaiser Permanente in Southern California we
don’t currently offer NIPT to low risk women, but are constantly evaluating the technology and
may offer it to all women in the future.”
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Common question #5
Patient: “I’m so confused! I don’t know what to do!”
Provider: “We have many resources to help you make your decision. If after reviewing them you need more information, I can also refer you to our local genetics department for a consultation.”
• EMMI module sent to all pregnant women• Decision Tree, Choices Booklet, KP NCAL video on
prenatal testing, other video options.• Genetics website : http://kp.org/scal/genetics
Esther Friedrich, MD – November 2018 – Interregional Symposium
Decision Tree for Prenatal TestingDo I want to know if my baby has a birth defect?*
Esther Friedrich, MD – November 2018 – Interregional Symposium
Fetal RHD determination:
• Most rh negative women: deletion of RHD gene on
chromosome 1
• NIPD avoids invasive procedures potentially leading to isoimmunization
• RHD gene absent in rh negative women; any
detection of gene in cffDNA means: fetus is Rh pos.
• Automated robotic system: sensitivities up to
99% @ 28 wks
(van der Schoot, 2004; Geifman-Holtzman, 2006)
Non-invasive prenatal
diagnosis
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Fetal sex determination:
• Indicated in women at risk for x-linked genetic disorder, or
CAH [potential development ambiguus genitalia] e.g.
Duchenne muscular dystrophy
• Advantage: early determination, option of termination of affected fetus, or avoidance of invasive procedure in
female fetus
• Best results: real time PCR for fetal SRY or DYS14 areas in cffDNA; NIPT
• Multiple studies show accuracy up to 99% after 7-10 wks
Moise et al, Prenat Diagn. 2013 Jan; 33(1):95-101
Non-invasive prenatal
diagnosis
Esther Friedrich, MD – November 2018 – Interregional Symposium
Prenatal Diagnosis
• Serum Screening – California Prenatal Screening Program
• Non-Invasive Prenatal Screening
• Other important Blood tests
• Genetic Ultrasound– First Trimester
– Second Trimester
– Prenatal Dysmorphology, MRI, 3D and 4D US
• Invasive Diagnosis– Amnio, CVS, PUBS
– Karyotyping, FISH, PGD
– Single Genes
– Metabolic Disease
– Microarray, Gene Sequencing
Esther Friedrich, MD – November 2018 – Interregional Symposium
Other blood test/screening
opportunities
• CF
• SMA
• Ashkenazi Jewish Screening
• Fragile X
• Blood disorders
(thalassemia, hemophilia, sickle cell etc)
• Metabolic disorders
• Neonatal screening,
(standard versus expanded)
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Cystic Fibrosis
– Carrier frequency 1:29
(North American Caucasians, Ashkenazi Jewish: 1:24, 94%)
– Testing sensitivity • in Caucasians 88% Carrier 1:25
• In Hispanics 72% Carrier 1:58
• In African American 64% Carrier 1:61
• In Asians 49% Carrier 1:94
– NIH recommended screening in 1997
– ACOG and ACMG recommended screening in
Oct 2001; common panel includes 23-84 mutations,
over 2000 are known
Esther Friedrich, MD – November 2018 – Interregional Symposium
SMA
(Spinal Muscular Atrophy)
– Affects ~ 1:10,000 newborns, progressive
muscle weakness and early death
• Caused by a mutation in the SMN1 gene, types 1 and 2 are known
• Recessive inheritance pattern
• Carrier frequency 1:40 – 1:60 in all
populations
• Reliable DNA testing is available, only ~10%
of carriers will be missed
• ACMG recommends population screening as of 11/2008; ACOG does as of 2017
Esther Friedrich, MD – November 2018 – Interregional Symposium
Carrier screening for Spinal muscular
atrophy
• Carrier screening for spinal muscular atrophy can now be ordered within HC (as of 9/20/18)
– Autosomal recessive disorder
– Carrier frequency (most populations): 1/40 – 1/60– Incidence: ~1/6,000 -1/10,000 live births
• SMA carrier screening should be offered to all prenatal patients at prenatal registration and to pts considering future pregnancies
• HealthConnect order: SPINAL MUSCULAR ATROPHY, SMN1 AND SMN2, CARRIER TESTING, 81401L
• OB providers’ SmartPhrases have been updated to include SMA:
– GENETICOBETHNICITYSCREENING and GENETICOBETHNICITYSCREENINGCLINICIANFOLLOWUP
• Member education handouts available in KP Clinical Library October 2018
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Hemoglobinopathies
• Hemoglobinopathies Carrier Frequency
Sickle cell 1:10 – 1:12 in AA
Hgb C 1:40 in AA
B Thalassemia 1:50 AA; 1:30 med.
α Thalassemia 1:25 in SEA
• Hemoglobin electrophoresis recommended for
prenatal screening in individuals of high risk ethnic background
• Electrophoresis if MCV < 80 in lower risk group
Esther Friedrich, MD – November 2018 – Interregional Symposium
Ashkenazi Jewish
screening
• Screening Panels for the most common disorders
are available, e.g. Quest laboratories, Genzyme:
• Bloom Syndrome
• Canavan disease
• Cystic Fibrosis
• Familial Dysautonomia
• Fanconi anemia group C
• Gaucher Disease
• Niemann-Pick disease A and B
• Tay-Sachs disease
An expanded Ashkenazi Jewish carrier screening
panel (10 conditions)
available when bothmembers of a couple are
AJ➢ Not orderable within
HealthConnect➢ Samples are sent out to
GeneDx
➢ Refer AJ/AJ couples to
Genetics or OB providers can fill out GeneDx lab
form
Esther Friedrich, MD – November 2018 – Interregional Symposium
Fragile-X syndrome
• Most common cause of mental retardation
in males. (< in females). Carrier ~1:130-250
• Phenotypic features
– Males: mental retardation, coarse facial
features, macroorchidism
– Females: no distinctive phenotype, variable
mental retardation; premutation: 25% POF
– Later life: fragile x tremor/ataxia syndrome
• Inheritance ~ X linked “dominant”, FMR1 gene (Xq27.3), expansion syndrome, no new mutations, all affected
individuals inherit gene from carrier parent
• ACOG CO #469 10/2010
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Member Education
• Member education handouts pre-test and post-test screen positive
– English can be ordered and Spanish print on demand (will
be in Clinical Library as well).
• New “infographic style” for general carrier screening
pamphlet pending
– English expected 10/2018, Spanish coming soon
Esther Friedrich, MD – November 2018 – Interregional Symposium
Expanded Carrier Screening
• Laboratories such as Counsyl and Natera offer
expanded carrier screening for 100s of genetic disorders
• Most of these disorders are very rare
• Offered for consanguineous couples, as previously noted
• Testing of partners can be expensive if the patient tests
positive for one or more conditions
• Expanded carrier screening is not recommended for the general population at this time and is not covered by KP
• If testing is requested, patients should be directed to
seek testing outside KP at their own expense
Esther Friedrich, MD – November 2018 – Interregional Symposium
Overview
• Diagnosis vs Screening
• Genetic Basics,Terminology & Disease
• Genetic Counseling
• Prenatal Screening & Diagnosis– Serum Screening and Blood tests
– Genetic Ultrasound
– Invasive Diagnosis
– Preconception
• Future direction
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Esther Friedrich, MD – November 2018 – Interregional Symposium
BREAK
Esther Friedrich, MD – November 2018 – Interregional Symposium
Prenatal Diagnosis
• Serum Screening – California Prenatal Screening Program
• Non-Invasive Prenatal Screening
• Other important Blood tests
• Genetic Ultrasound– First Trimester
– Second Trimester
– Prenatal Dysmorphology, MRI, 3D and 4D US
• Invasive Diagnosis– Amnio, CVS, PUBS
– Karyotyping, FISH, PGD
– Single Genes
– Metabolic Disease
– Microarray, Gene Sequencing
Esther Friedrich, MD – November 2018 – Interregional Symposium
Guidelines
ACOG, ACR, AIUM, NICHD, SRU, SMFM
Reaffirmed 2018
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Equipment and
Documentation
Equipment– Abdominal
3 or 5 MHz Transducer
- Abdominal
2 or 2.25 MHz in obese patients
– Vaginal
5 - 10 MHz Transducer
Documentation– Permanent record
– Image retention
– Appropriate labeling
– Written Report
AIUM= American Institute for Ultrasound in Medicine
Esther Friedrich, MD – November 2018 – Interregional Symposium
Ultrasound Types
What Are They?
First Trimester Ultrasound
Basic = Standard Second- or Third Trimester Ultrasound
Limited = Performed in certain, defined circumstances
Comprehensive = Specialized “Indicated for a patient suspected of carrying an abnormal fetus by: history, clinical evaluation, or prior ultrasound exam”
Esther Friedrich, MD – November 2018 – Interregional Symposium
WHO DOES THE EXAM?
Basic - “Peformed or reviewed by appropriately trained operator”
Limited - “Performed by ultrasonographer or specially trained personal”
Comprehensive - “Performed by an operator with experience and expertise in such scanning”
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Ultrasonographic
Visualization of Pregnancy
Part I
Esther Friedrich, MD – November 2018 – Interregional Symposium
First-Trimester Exam
Abdominal or vaginal US
Gestational sacYolk Sac
Embryo
Crown-Rump-LengthPresence or absence of cardiac activity Fetal number
Amnionicity, ChorionicityUterus, cervix, adnexal structures, cul-de-sac
YS
First Trimester Ultrasound ~8 weeks
CRL
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Cardiac Activity
Measure by M-mode at < 8 weeks
Measure by Doppler at > 8 weeks
Doppler = Heat
Esther Friedrich, MD – November 2018 – Interregional Symposium
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First Trimester Guidelines
Multiple Pregnancies
– Report only when multiple embryos
seen
– Report chorionicity and amnionicity• More reliable than at any other time in pregnancy
– # yolk sacs “sometimes” = # amniotic sacs
Crown-rump more reliable gestational age predictor than sac
size
Esther Friedrich, MD – November 2018 – Interregional Symposium
Triplets
Monochorionic,
diamniotic
Dichorionic,
diamniotic
1
2
3
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Monoamniotic, monochorionic twins, 7 weeks
Dichorionic, diamniotic twins, 7 weeks, 3D US
What exactly is a nuchal translucency?Nicolaides
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Nicolaides
Esther Friedrich, MD – November 2018 – Interregional SymposiumTris. 13
Midline facial defect
Hygroma
Omphalocele
Esther Friedrich, MD – November 2018 – Interregional Symposium
Genetic syndromes
with enlarged nuchal fold
Jarcho-Levine syndrome
Joubert syndrome
Nance-Sweeney syndrome
Noonan syndrome
Smith-Lemli-Opitz syndrome
Spinal muscular dystrophy
Thanatophoric dysplasia
Trigonocephaly ̀ C´ syndrome
VATER association
Achondrogenesis
Achondroplasia
Beckwith-Wiedemann syndrome
Camptomelic dysplasia
EEsC yndrome
Fryns` syndrome
GM1 gangliosidosis
Hydrolethalus syndrome
Meckel-Gruber syndrome
Roberts syndrome
Zellweger syndrome
Fetal Akinesia Deformation
Sequence
Osteogenesis imperfecta
Asphyxiating thoracic dystrophy
Blomstrand osteochondrodysplasia
Short rib-polydactyly syndrome
type I
Short rib-polydactyly syndrome
type IV
Diatomatomelia
Di George syndrome
Perlman syndrome
Alpha-thalassaemia
Spondylocostal dysostosis
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Early hydrops
CRL
Esther Friedrich, MD – November 2018 – Interregional Symposium
First trimester ultrasound
Total of 200,868 pregnancies, 871 trisomy 21:
Increased NT 76.8% T21 detection; 4.2% false positive
Total of 44,613 pregnancies, 215 trisomy 21:
NT + serum markers 87% T21 detection, 5% false positive
Total of 15,822 pregnancies, 397 trisomy 21:
NT + nasal bone 69% T21 detection, 1.4% false positive
“Nuchal translucency and other first trimester sonographic markers of chromosomal
abnormalities” Nicolaides, K; Am J Obstet Gynecol (2004) 191, 45-67
First trimester ultrasound
“First Trimester Screening for Chromosomal Abnormalities” Nicolaides, K; Seminars Perinat (2005) 29:190-194
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Tricuspid
Regurgitation
Assessment:
Population 77 T21, 232
normal fetuses:TR in 57 = 74% T21; 16 =
6.9% normals
No significant
differences in maternal serum levels
in pregnancies with or
without T21 and evidence of TR
“Screening for trisomy 21 by fetal tricuspid regurgitation, NT and
maternal serum f-β HCG and PAPP-A at 11+0 to 13+6 weeks”
Falcon, O; Nicolaides, K et al; Ultrasound Obstet Gynecol 2006; 27: 151-155.
Faiola et al, 2005
First trimester ultrasound
Esther Friedrich, MD – November 2018 – Interregional Symposium
Abnormal Ductus Venosus Flow Assessment:
Found in ~80% of T21 fetuses, 5% chromosomally
normal
“First Trimester Screening for Chromosomal Abnormalities” Nicolaides, K; Seminars
Perinat (2005) 29:190-194
First trimester ultrasound
Esther Friedrich, MD – November 2018 – Interregional Symposium
Relative risk of a congenital heart defect in relation
to first trimester nuchal fold thickness:
3 mm 5 / 1000
4 mm 27 / 1000
5 mm 54 / 1000
6 mm 266 / 1000Nicolaides, Snijders
First trimester ultrasound
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Ultrasonographic
Visualization of Pregnancy
Part II
Esther Friedrich, MD – November 2018 – Interregional Symposium
What are Indications for a Standard
Second or Third -Trimester Exam ?
ACOG has a list of at 29 indications, initially adapted from the NIH in 1984, since then steadily increased:
Esther Friedrich, MD – November 2018 – Interregional Symposium
What Is a Standard Second- or Third-
Trimester Exam ?
Amniotic Fluid Volume Assessment
Fetal PresentationCardiac Activity
Fetal biometry
Fetal weight estimationAnatomic Survey
Placental Localization Maternal cervix and adnexa if technically feasible
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Esther Friedrich, MD – November 2018 – Interregional Symposium
When Is a Limited Exam
Appropriate?
Amniotic Fluid Volume Assessment
Amniocentesis Guidance
External Cephalic Version
Presentation
Confirmation of IUFD
Placental Localization (if bleeding)
Esther Friedrich, MD – November 2018 – Interregional Symposium
When Is a Specialized Exam
Appropriate?
Suspected fetal anomaly (clinical, biochemical, based on history or
results of prior exam)
Fetal Doppler
Fetal Echocardiogram
Biophysical Profile
Additional biometric studies
Esther Friedrich, MD – November 2018 – Interregional Symposium
What do we want to see?
• Chromosomal malformations
• Structural malformations
• Fetal disease
• Feto-maternal disease
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What are we unable to see?
•Mental retardation
•Most metabolic disorders
•Most single gene defects
•Ca. 20-25% of chromosomal malformations
Esther Friedrich, MD – November 2018 – Interregional Symposium
What Is a Standard Second- or Third-
Trimester Exam ?
Amniotic Fluid Volume Assessment
Fetal PresentationCardiac Activity
Fetal biometry
Fetal weight estimationAnatomic Survey
Placental Localization Maternal cervix and adnexa if technically feasible
Esther Friedrich, MD – November 2018 – Interregional Symposium
Fetal Biometry
Second Trimester
Biparietal Diameter
Head Circumference
Abdominal Circumference
Femur Length
Humerus Length
Cerebellar Diameter
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Biparietal Diameter
Landmarks– Midline Falx
– Thalamic symmetry on either side of falx
– Cavum Septum pellucidum
Measure leading edge to leading edge– “Outer edge to inner edge”
No cerebellum or orbits visualized
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Esther Friedrich, MD – November 2018 – Interregional Symposium
Cerebellar Diameter
Obtained by starting with BPD view, then
visualizing posterior fossa
Requires maintaining visualization of thalami
Tends to be “spared” as a predictor of gestational age in the presence of IUGR
Between 14 - 20 weeks, measurement in
mm = GA in weeks
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Femur/Humerus Length
Measure perpendicular to ultrasound beam (femur ends at
03:00 and 09:00)
Third trimester: distal femoral
epiphysis visible
Humerus equally so
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Esther Friedrich, MD – November 2018 – Interregional Symposium
Abdominal Circumference
Landmarks
– Circular circumference
– 90° transverse image of spine
– Stomach in left abdomen
– Umbilical portion of left portal vein:• equidistant from lateral sides of body
• not contiguous with anterior abdominal wall
• Spine cannot be at 12:00 position
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Esther Friedrich, MD – November 2018 – Interregional Symposium
Esther Friedrich, MD – November 2018 – Interregional Symposium
What Is a Standard Second- or Third-
Trimester Exam ?
Amniotic Fluid Volume Assessment
Fetal PresentationCardiac Activity
Fetal biometry
Fetal weight estimationAnatomic Survey
Placental Localization Maternal cervix and adnexa if technically feasible
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ANATOMIC SURVEY:
What Must It Include?
Cerebral Ventricles
Four Chamber Cardiac View, Cardiac Position
Spine
Stomach
Bladder
Kidneys
Anterior Abdominal Wall
Umbilical Cord Insertion
Posterior Fossa
Nuchal Fold
Extremities
if technically feasible,
cardiac outflow tracts should be visualized
Esther Friedrich, MD – November 2018 – Interregional Symposium
ANATOMIC SURVEY:
What Must It Include?
Esther Friedrich, MD – November 2018 – Interregional Symposium
•Thickened nuchal fold RR x 18,6
•Severe structural heart defects
•Duodenal stenosis RR x 25
•Hydrocephalus
•Omphalocele
Due to high specificity and low false positive rate, those markers have a high positive predictive value – even within
the low risk population Benacerraf et al, ´00,
Second trimester
ultrasound
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Likelihood Ratios and Soft Markers –Nicolaides 2003
5.20.7932.9661/9384(0.65%)
75/350(21.4%)
Major Defect
3.00.8721.1758/9227(0.6%)
39/293(13.3%)
Echogenic bowel
1.10.756.41401/9199(4.4%)
75/266(28.2%)
Echogenic focus
1.00.856.77242/9331(2.6%)
56/319(17.6%)
Hydronephrosis
1.60.627.94486/9331(5.2%)
132/319(41.4%)
Short Femur
4.10.6822.76136/9254(1.5%)
102/305(33.4%)
Short humerus
9.80.6753.0559/9331(0.6%)
107/319(33.5%)
Nuchal fold
LR for isolated marker
Negative LRPositive LRNormalTrisomy 21Sonographic Marker
Esther Friedrich, MD – November 2018 – Interregional Symposium
Down syndrome
• Down Syndrome – Trisomy 21– 1:700 newborns
– Moderate mental retardation,
congenital cardiac defects (40%),
GI obstruction, typical facies,
median survival 50 years
– 95% non-disjunction
(95% maternal, usually meiosis I)
– 3% translocation (half are de novo)
– 2% mosaic (may modify phenotype
but not reliable for counseling)
Esther Friedrich, MD – November 2018 – Interregional Symposium
•Nuchal thickening 38 % (80%)
•Cardiac defect 26% (40%)
•Mild hydronephrosis 30%
•short femur 28%
•Abnormal hands and feet 25% (60%)
•SGA 20%
•Hydrops 20%
•Ventriculomegaly 16%
•Brachycephaly 15%
•Duodenal stenosis 8%
US findings in Trisomy 21
n= 155 (Nicolaides FMF)
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Esther Friedrich, MD – November 2018 – Interregional Symposium
stomach
Dilated
duodenum
Trisomy 21
Classic „Double Bubble“ with duodenal stenosis
Esther Friedrich, MD – November 2018 – Interregional Symposium
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Perinatology.com
Esther Friedrich, MD – November 2018 – Interregional Symposium
Edwards syndrome
• Edwards Syndrome -
Trisomy 18
– 1:6,000 newborns, 80% female
– Multiple anomalies,
especially cardiac, renal,
hand posturing
– Death
• 30% by 1st month, 50%
by 2nd month, 90% by 12th month
– 85-90% non-disjunction
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•SGA 74% (>50%)
•Abnormal hands and feet 72% (>50%)
•Heart defects 52% (>50%)
•Micrognathia 53% (>50%)
•Abnormally shaped head 54% (>50%)
•Choroid plexus cysts 47% (<10%)
•Omphalocele 31% (10-50%)
•Talipes 30% (10-50%)
•Brachycephalus 29% (>50%)
•Mild Hydronephrosis 16% (10-50%)
US findings in trisomy 18
n= 137 (Nicolaides FMF)
Tris. 18
Complete cystic choroid plexus
Tris. 18
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Chrom. normal
Large omphalocele containing liver
Omphalocele
Esther Friedrich, MD – November 2018 – Interregional Symposium
Tris. 18
Persistently overlapping fingers
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Overlapping fingers
Esther Friedrich, MD – November 2018 – Interregional Symposium
Pätau syndrome
• Pätau syndrome –
Trisomy 13
– 1:12,000 newborns
– Multiple anomalies, clefts polydactyly,
microophthalmia,
omphalocele, holoprosencephaly, NTDs
– Death
• 45% 1st month, 90% by 6th month
– 80% non-disjunction
Zafira – 6 months old
www.livingwithtrisomy13.or
g
Esther Friedrich, MD – November 2018 – Interregional Symposium
•SGA 61% (<50%)
•Abnormal hands and feet 52% (>50%)
•Cardiac defects 43% (>80%)
•Holoprosencephaly 39% (>50%)
•Facial clefts 39% (60-80%)
•Mild hydronephrosis 37% (<50%)
•enlarged cisterna magna 25% (<50%)
•Microcephaly 24% (>50%)
•Brachycephalus 26% (>50%)
•Nuchal thickening 22% (>50%)
postpartum
US findings in trisomy 13
n= 137 (Nicolaides FMF)
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Tris. 13
singular ventricle
Ethmocephaly
Cebocephaly
Esther Friedrich, MD – November 2018 – Interregional Symposium
4-chamber-view:
40 % of CHD
Outflow-tract of the large vessels:
additional 20-30 % of CHD
Second trimester
ultrasound
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Jeanty, et al
Association of cardiac defects
with genetic disease
Esther Friedrich, MD – November 2018 – Interregional Symposium
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Neural Tube Defects
• Etiology:
– Multifactorial Origin
– Syndromes – single gene
• Meckel-Gruber, chromosome 17, autosomal-recessive
– Chromosomal disorders
• T13, T18, ring chromosomes, triploidy
– Teratogens
• Valproic Acid, Thalidomide, MTX, increased core temp?
– Metabolic deficiencies in Mom
• Diabetes mellitus
• Folic acid deficiency
– Others (eg Amnion Band Syndrome)
Esther Friedrich, MD – November 2018 – Interregional Symposium
Ultrasound vs
Amniocentesis
Norem, C.T. et al. ObGyn 106(4):747-752, 2005
• N = 130 cases with no MSAFP available at time of
scan
• Detection rate 96%
– Included all gestational ages
– Only 1/3 of cases done at tertiary centre
• N = 189 total cases at N. Cal. Kaiser during 7 year
period
– 38% of cases of spina bifida occurred in
women with negative MSAFP screening
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Anencephaly
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Intact facial
bones,
„frog face“
Esther Friedrich, MD – November 2018 – Interregional Symposium
Fetal Dysmorphology
• Attempted visualization soft tissue
structures prenatally:
– Chin
– Tongue
– Ears
– Epicanthal eyefolds
– Hands (creases)
• Few published case reports of
successful use [Mangione Prenat Diagn. 2003 Oct;23(10):810-8.]
• Currently not standard of care
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Esther Friedrich, MD – November 2018 – Interregional Symposium
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Esther Friedrich, MD – November 2018 – Interregional Symposium
BREAK
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Overview
• Diagnosis vs Screening
• Genetic Basics,Terminology & Disease
• Genetic Counseling
• Prenatal Screening & Diagnosis– Serum Screening and Blood tests
– Genetic Ultrasound
– Invasive Diagnosis
– Preconception
• Future direction
Esther Friedrich, MD – November 2018 – Interregional Symposium
Prenatal Diagnosis
• Serum Screening – California Prenatal Screening Program
• Non-Invasive Prenatal Screening
• Other important Blood tests
• Genetic Ultrasound– First Trimester
– Second Trimester
– Prenatal Dysmorphology, MRI, 3D and 4D US
• Invasive Diagnosis– Amnio, CVS, PUBS
– Karyotyping, FISH, PGD
– Single Genes
– Metabolic Disease
– Microarray, Gene Sequencing
Esther Friedrich, MD – November 2018 – Interregional Symposium
Prenatal Diagnosis
ACOG Practice Bulletin 2007: option of invasive testing
should be available to
ALL
women, regardless of age
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Amniocentesis
• Done @ 15 wks – term
• Amniotic fluid – Enzymes
– Proteins
– Hormones
– culture, PCR (infections)
– Delta OD 450 (rh-disease)
– Lung maturity
– Genetic (cell culture)
• Procedure risk ~ 1/3-500 loss (twins are different)
• Early amnio has higher risk (13-15 wks)
Esther Friedrich, MD – November 2018 – Interregional Symposium
Chorion Villous Sampling
• Done @ 11wks-13wks
• Chorionic villi– Karyotype only
– Higher incidence of mosaicism
• Confined placental mosaicism
– Vaginal or abdominal procedure
• Procedure risk ~ 1/200 loss
• Early procedure associated with limb defects
Esther Friedrich, MD – November 2018 – Interregional Symposium
Periumbilical Blood
Sampling
Done after 18-20 weeks
• Rarely done for genetic
purposes
• does not require cell culture,
fast!
• Procedure risk ~ 1-2/100 loss
• Usually with therapeutic
intent
(transfusion,
medication application)
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Regional Amniocentesis Trends2010 – 2018 YTD*
18361710
1506
1025
597522
442 452354
0
200
400
600
800
1000
1200
1400
1600
1800
2000
2010 2011 2012 2013 2014 2015 2016 2017 2018*
*2018 YTD: Jan – Sept 2018
Esther Friedrich, MD – November 2018 – Interregional Symposium
Regional CVS Trends2010 - 2018 YTD*
370 364 370
291
196
244 251
283
193
0
50
100
150
200
250
300
350
400
2010 2011 2012 2013 2014 2015 2016 2017 2018**2018 YTD: Jan – Sept 2018
Esther Friedrich, MD – November 2018 – Interregional Symposium
Trends in Abnormal Diagnostic
Testing Results
2012 (pre-NIPT) to 2017:
62% fewer diagnostic tests detected a
greater number of abnormal karyotypes.
# Abnormal
karyotypes T21 T18 #diagnostic procedures
2012 120 63 29 1936
2017 154 78 31 738
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Overview
• Diagnosis vs Screening
• Genetic Basics,Terminology & Disease
• Genetic Counseling
• Prenatal Screening & Diagnosis– Serum Screening and Blood tests
– Genetic Ultrasound
– Invasive Diagnosis
– Preconception
• Future direction
Esther Friedrich, MD – November 2018 – Interregional Symposium
Preimplantation Genetic
Screening and Diagnosis
• Utilizes a single cell, 8-cell stage or blastomere biopsy
• Only with IVF; impact on pregnancy outcome controversial
• Selective karyotype or array CGH
• Able to detect ~ 40% single gene disorders testable
(know what to look for; choose which test to use!)
• High misdiagnosis rate (> 3%) with PCR
• Allele dropout and postzygotic events;
even trisomies can occur post PGD,
trisomic rescue
• Mosaicism stays undetected by FISH
• May have new utility with use of sequencing technologies
• ACOG CO #430, 3/2009Fiorentino et al, Hum Reprod. 2014 Oct
21. pii: deu277. [Epub ahead of print]
Esther Friedrich, MD – November 2018 – Interregional Symposium
Present day challenges
• Personalized
medicine
• Patient expectations
• Screening and diagnostic test
marketed by commercial
companies
• Rapidly evolving new
technologies
• Ethical concerns www.genomemag.com
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Genetic Microarray
• Increasingly used prenatally
• population selection bias: referral for postnatal array-CGH mostly due to dysmorphic features,
behavioral abnormalities or DD, not available to the
prenatal population
• Indicated for unexplained US anomalies, stillbirth,
miscarriage [?], routine [?]
Shaffer et al, “Comparison of microarray-based detection rates for
cytogenetic abnormalities in prenatal and neonatal specimens ”, Prenatal
Diagnosis 2008
Wapner et al: N Engl J Med. 2012 Dec 6;367(23):2175-84. doi:
10.1056/NEJMoa1203382.
Chromosomal microarray versus karyotyping for prenatal diagnosis.
Esther Friedrich, MD – November 2018 – Interregional Symposium
• Targeted versus SNP array
• Targeted: company specific “chip” of probes specific to disease causing mutations
• Advantage: less CNV’s of unknown significance
• Diagnosis can be limited to desired location
• Prenatal targeted arrays widely available, eg
GeneDx with ~150 common or novel microdeletions and –duplications
• Disadvantage: not usually detecting uniparental disomy, imprinting and methylation disorders unless
specified
• SNP/Genome wide: fills the gaps above
Genetic Microarray
Esther Friedrich, MD – November 2018 – Interregional Symposium
Cytogenomic Microarray Analysis
(CMA)CMA: Cytogenomic Microarray Analysis detects DNA copy number gains and losses associated with unbalanced
chromosomal aberrations
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Cytogenomic Microarray Analysis to replace Standard Karyotyping following prenatal diagnostic
procedures as standard of care?
• In December 2012, Ronald Wapner, MD published an article in the NEJM showing that in the context of prenatal diagnosis, CMA identified additional, clinically significant cytogenetic results as compared to standard karyotyping
• In 2013, the ACMG revised their Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications. They listed the advantages and limitations of CMAs
• In 2013, ACOG published Committee Opinion Number 581 on the Use of Chromosomal Microarray Analysis in Prenatal Diagnosis, which included the information to share with patients before prenatal CMA
California Department of Public Health
Esther Friedrich, MD – November 2018 – Interregional Symposium
Indications for MA as a “Soft” Authorized Follow-up Service through the CA PNS Program
• The woman must be seen at a PDC in the Second Trimester (between 15 and 24 weeks gestation), receive Genetic
Counseling, an Ultrasound performed by an approved
Consultative Sonologist and consent to have an Amniocentesis provided by an approved Amniocentesis
Practitioner
• The Second Trimester Ultrasound must find a designated
fetal structural anomaly
• The woman must consent to Microarray in lieu of Standard
Karyotyping
California Department of Public Health
Esther Friedrich, MD – November 2018 – Interregional Symposium
Second Trimester Ultrasound Anomalies where MA is Authorized as an Option in Lieu of Standard Karyotyping
Central Nervous System
Agenesis/Hypoplasia of Corpus Callosum
Arnold Chiari Malformation
Cerebellar Hypoplasia
Dandy WalkerEncephalocele
Holoprosencephaly
Hydrocephalus NOT with spina bifida (unknown
etiology)
Meckel Gruber
Mega Cisterna MagnaPentalogy of Cantrell
Porencephaly
Ventriculomegaly
Face
Absent Nasal BoneCleft Lip
Cleft Lip & Palate
Cleft Palate
Micrognathia
NeckCystic Hygroma
Nuchal Fold (> 5 mm)
Heart/Lung
Cardiac Defect- Abnormal Outflow Tracts
Cardiac Defect- Aortic Valve Stenosis
Cardiac Defect- Atrial Septal Defect (ASD)
Cardiac Defect- CardiomegalyCardiac Defect- Coarctation of Aorta
Cardiac Defect- Truncus Arteriosus
Cardiac Defect- Dextrocardia/Heart on right
side
Cardiac Defect- Endocardial Cushion Defect/
A-V canalCardiac Defect- Ebstein Anomaly
Cardiac Defect- Enlarged Atrium
Cardiac Defect- Hypoplastic Left Heart
Cardiac Defect- Hypoplastic Right Ventricle
Cardiac Defect- Pericardial Effusion
Cardiac Defect- Pulmonary Valve Atresia/Stenosis
Cardiac Defect- Tetralogy of Fallot
Cardiac Defect- Total Anomalous Pulmonary
Venous Return
Cardiac Defect- Transposition of the Great VesselsCardiac Finding- Tricuspid Regurgitation (TR)
Cardiac Defect- Tricuspid Valve Atresia/Stenosis
Cardiac Defect- Ventricular Septal Defect (VSD)
Pleural Effusion
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Second Trimester Ultrasound Anomalies where MA is Authorized as an Option in Lieu of Standard Karyotyping
Abdomen
Absent Stomach
Ascites/Anasarca/Edema
Diaphragmatic Hernia
Double BubbleDuodenal Obstruction
Omphalocele
Small Stomach
Skeletal System
Skeletal DysplasiaSevere Scoliosis Lower extremity- Abnormal in position or number
of
bones
Lower extremity- Unilateral Clubfoot
Lower extremity- Bilateral ClubfeetUpper extremity- Abnormal in position or
number of
bones
Upper extremity- Absent bones
Upper extremity- Arthrogryposis Multiplex
CongenitaUpper extremity- Clenched hands
Upper extremity- Polydactyly
Kidney/Urinary Bladder/Pelvis
Absent Bladder
Absent Kidney-Unilateral
Absent Kidneys-Bilateral
Dilated Urinary BladderEchogenic kidneys
Empty Urinary Bladder
Enlarged kidneys
Hydronephrosis
Multicystic Dysplastic kidneys
Pelvic cystsPotter syndrome
Pyelectasis
Renal cysts
Size/Growth/Overall Appearance
Generalized EdemaHydrops Fetalis
Intrauterine Growth Retardation (IUGR)
Amniotic Fluid Volume
Severe Oligohydramnios
Severe Polyhydramnios
Umbilical Cord
2 Vessel Cord/Single Umbilical Artery
Esther Friedrich, MD – November 2018 – Interregional Symposium
Targeted Mutation
analysis
• Suspected specific disorder based on prenatal US findings and normal karyptype
• Select cases may warrant additional prenatal testing, eg
• Noonan Syndrome (8 genes: BRAF, HRAS, KRAS,
MAP2K2, PTPN11, RAF1, SOS1)
• Holoprosencephaly (SHH, SIX3, TGIF, ZIC2)
• Hydrocephalus (L1CAM)
• Skeletal dysplasias (some labs offer panels)
• Cardiomyopathy (>50 genes and counting)
• Prenatal mutation panels are available, eg GeneDx, with summary of US and prenatal findings
• COST?
Esther Friedrich, MD – November 2018 – Interregional Symposium
• Multiple labs and companies developed “exome
sequencing”, clinically available
• Only sequences short, functionally important
sequences of DNA (Exons) representing regions in
genes translated into proteins
• Human genome: ~180,000 exons (50 million DNA
bases), ~1.5% of the human genome; protein coding regions are estimated as ~85% of disease
causing mutations.
• Multiple companies offer exome sequencing at $699-$999 in addition to clinical labs
Sequencing
Yang et al, N Engl J Med 10/17/2013, Vol 369(16):1502-1511
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Overview
• Diagnosis vs Screening
• Genetic Basics,Terminology & Disease
• Genetic Counseling
• Prenatal Screening & Diagnosis– Serum Screening and Blood tests
– Genetic Ultrasound
– Invasive Diagnosis
– Preconception
• Future direction
Esther Friedrich, MD – November 2018 – Interregional Symposium
• 2007 the internet –based company 23andme
offers gene analysis & risk assessment for everyone
• First: $999 + $45 S&H, now $99: DNA kit for saliva
samples
• Using SNP-based technology for ~ 1.8 million data points, not full sequencing
• Allows comparison of DNA to family & friends, provides maps of genetic ancestry
• Google is one of the main investors
• 2013 the FDA temporarily forced discontinuation of
personal genome service for regulatory reasons
• www.23andme.com
Science Fiction?
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The future
Esther Friedrich, MD – November 2018 – Interregional Symposium
Science Fiction?
• Gene
pioneer Craig
Venter published his
own entire genome in
full sequence
on the internet in
9/2007
Esther Friedrich, MD – November 2018 – Interregional Symposium
• Since: J.Craig Venter Institute
• First synthetic genome
• High throughput Sequencing (first: shotgun
sequencing) in Human Genome Project Race
• Massively parallel genomic sequencing
• Race/Competition for first commercially available
“$1000 genome” lead by Complete Genomics, Knome, Beckman Coulter, (IBM, Google, Apple etc.)
• Competition lead to $100 Genome – single molecule, electrical real-time analysis without need
for complicated optics [“GENIA”/”IMEC/Panasonic”]
Science Fiction?
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Esther Friedrich, MD – November 2018 – Interregional Symposium
• PGD can now screen for >150 diseases prior to
implantation; many adult onset
• Major contributing genes for diabetes, heart disease,
cancer, mental illness, Parkinson’s, stroke, asthma are
being identified or already known
• Embryos selected by gender, eye, hair color and
“traits” – polymorphisms thought to be associated with athletic talent, musical talent etc
• Ethicists raise concerns:
• Eugenics
• Inequality
• Control
Reality
Esther Friedrich, MD – November 2018 – Interregional Symposium
• February 2014: Natera expanded Panorama NIPT
to include clinically significant microdeletions
• 22q11.2 deletion syndrome
• Angelman syndrome
• Cri-du-chat syndrome
• 1p36 deletion syndrome
• Prader-Willi syndrome
• Marketed as an “opt-out” addition
• Based on a small trial; all conditions with incidences of 1:1-2000 or less
Reality
Esther Friedrich, MD – November 2018 – Interregional Symposium
Kitzman et al
Sci Transl Med. Jun 6, 2012; 4(137): 137re76
Maternal plasma DNA sequencing reveals the
genome-wide genetic and mutational profile
of the fetus.
Reality
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Esther Friedrich, MD – November 2018 – Interregional Symposium
• May 21st, 2008:
Genetic Information Non-Discrimination Act (GINA)
• It is illegal for employers or insurances to discriminate
based on genetic information
= insurance or employment cannot be denied due to genetic
information (e.g. Carriers of cancer predisposing mutations
(HNPCC, BRCA, etc))
• Also 2008: first child born in UK selected NOT to
carry the BRCA mutation by PGD
• In utero gene therapy works in animal models
(eg Pompe’s disease, hemophilia B) but has not been
translated into clinical practice (Nature, 2005, 2010)
Reality
Reality?
Esther Friedrich, MD – November 2018 – Interregional Symposium
Take Home Message
• Prenatal genetic diagnosis AND screening:
increasingly complicated processes; multitude of
different strategies available to both MD and patient
• Genetic counselor = your best friend ! family history; testing and screening options; results
• The future moves rapid: Do NOT start ordering NIPT, array-CGH or targeted mutation analysis
without a geneticist or counselor involved
• Be prepared: your patient will ask about sequencing and cfDNA; both are commercially
available
• Next year: this talk will be entirely different
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Esther Friedrich, MD – November 2018 – Interregional Symposium
30 years ago
High risk patient and
pregnancy
Invasive Diagnostics
Esther Friedrich, MD – November 2018 – Interregional Symposium
Prenatal diagnostics today
High- and low-risk-patient
Path.Path.
PAPP-A,
ß-HCG
First-Trimester-Screening
WNL
WNL
WNL
Serum-
AFP
Quad-
Test
Path.
AC CVS
Path.
kayotype FISH array
sequence
Serum-ScreeningFirst-Trimester-Scan Second-Trimester-Scan
genetic Ultrasound
Invasive Diagnostics
Non-invasive TestingNIPT Genetic counseling
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Select References
• NSGC practice guideline: prenatal screening and diagnostic testing options for chromosome aneuploidy. Wilson KL,
Czerwinski JL, Hoskovec JM, Noblin SJ, Sullivan CM, Harbison A, Campion MW, Devary K, Devers P, Singletary CN. J Genet
Couns. 2013 Feb;22(1):4-15. doi: 10.1007/s10897-012-9545-3. Epub 2012 Nov 22.
• Effects of changes in prenatal aneuploidy screening policies in an integrated health care system. Norton ME, Nakagawa S,
Norem C, Gregorich SE, Kuppermann M. Obstet Gynecol. 2013 Feb;121(2 Pt 1):265-71. doi:
http://10.1097/AOG.0b013e31827e5c85.
• Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Bianchi DW, Platt LD, Goldberg JD,
Abuhamad AZ, Sehnert AJ, Rava RP; MatErnal BLood IS Source to Accurately diagnose fetal aneuploidy (MELISSA) Study
Group. Obstet Gynecol. 2012 May;119(5):890-901. doi: 10.1097/AOG.0b013e31824fb482. Erratum in: Obstet Gynecol. 2012
Oct;120(4):957.
• Early anatomy ultrasound in women at increased risk of fetal anomalies. Lim J, Whittle WL, Lee YM, Ryan G, Van Mieghem T.
Prenat Diagn. 2013 May 9:1-6. doi: 10.1002/pd.4145.
• Chromosomal microarray versus karyotyping for prenatal diagnosis. Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM,
Zachary JM, Savage M, Platt LD, Saltzman D, Grobman WA, Klugman S, Scholl T, Simpson JL, McCall K, Aggarwal VS, Bunke
B, Nahum O, Patel A, Lamb AN, Thom EA, Beaudet AL, Ledbetter DH, Shaffer LG, Jackson L. N Engl J Med. 2012 Dec
6;367(23):2175-84. doi: 10.1056/NEJMoa1203382.
• CA State Screening program: http://www.cdph.ca.gov/programs/gdsp/pages/default.aspx
• http://www.acog.org/Resources_And_Publications/Practice_Bulletins/Committee_on_Practice_Bulletins_--
_Obstetrics/Invasive_Prenatal_Testing_for_Aneuploidy #88, 2009
• http://www.acog.org/Resources_And_Publications/Practice_Bulletins/Committee_on_Practice_Bulletins_--
_Obstetrics/Screening_for_Fetal_Chromosomal_Abnormalities #77, 2011
•http://www.acog.org/Resources_And_Publications/Committee_Opinions/Committee_on_Genetics/Noninvasive_Prenatal_Testi
ng_for_Fetal_Aneuploidy # 545 12/2012
• Thompson & Thompson “Genetics in Medicine”, 7th Edition, 2007
• Women’s Health Review – A clinical update in Obstetric & Gynecology1st Edition, 2012
• Additional sources as marked in the presentation
•BUN trial Wapner et al, NEJM, 2003, multiple publications
•SURUSS trial Wald et al, BJOG, 2004, multiple publications
•FASTER trial Malone et al, NEJM, 2005, multiple publications
Esther Friedrich, MD – November 2018 – Interregional Symposium
Genetics
is available in your area
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Esther Friedrich, MD – November 2018 – Interregional Symposium
CA STATE PRENATAL SCREENING PROGRAM INFORMATION
PSR Contacts and Special Authorizations:
Jacqueline Avila (510) 412-6205
Cheryl Ikeda (510) 412-1475Bret Hutchinson (510) 412-3939
PDC Invoicing:
Nympha Valdezotto (510) 412-1479
California Department of Public Health
Esther Friedrich, MD – November 2018 – Interregional Symposium
Regional NIPT statistics
• Total number of specimens drawn in 2017: 10,040 (9,885
resulted)
– 91% AMA indication
– 8.6% increase over 2016
– 30 failed lab tests, increased from 7 in 2016. Likely caused by algorithm adjustments 6/2017
• Total number of abnormal NIPT results: 222 (2.2% abnormal results)
– decrease of 1% from prior year—likely due to elimination of “suspected” abnormality category
Esther Friedrich, MD – November 2018 – Interregional Symposium
Exercise 1
24 year old G1P0 presents with 29 year old husband for PNV.
Both are Caucasion.
She has bipolar disorder and mild
learning disabilities, he is healthy.
They wonder about prenatal screening
options.
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Exercise 1
They choose sequential integrated screening.
During their NT ultrasound an NT of 4.5 mm is noted.
How do you counsel the patient?
Esther Friedrich, MD – November 2018 – Interregional Symposium
Exercise 1
They undergo genetic counseling and choose to continue the pregnancy.
Anatomic US at 20 weeks shows bilateral EIF, mild pyelectasis and an AV canal
defect.
How do you counsel them?
Esther Friedrich, MD – November 2018 – Interregional Symposium
Exercise 1
They undergo genetic amniocentesis and the karyotype returns 47,XX+21.
They choose to continue the pregnancy and deliver an otherwise healthy baby
with classic features of Down syndrome at term.
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Exercise 2
4 years later they return with another pregnancy.
She is now 28 years old, G2P1 and reports a young half sibling with a
cardiac defect; he is 33 years old and has developed diabetes.
They wonder again about their prenatal screening options.
How do you counsel them?
Esther Friedrich, MD – November 2018 – Interregional Symposium
Exercise 2
They choose NIPT, which returns with a low risk.
They undergo detailed anatomy screening and fetal screening
echocardiogram and fetal Tetralogy of Fallot is suspected.
How do you counsel them?
Esther Friedrich, MD – November 2018 – Interregional Symposium
Exercise 2
They undergo genetic amniocentesis and the karyotype returns 46,XY.
Array CGH reveals a deletion 22q11.2
The couple decides to terminate the
pregnancy.
Maternal FISH reveals the same 22q11.2
deletion.
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Esther Friedrich, MD – November 2018 – Interregional Symposium
Exercise 3
The patient returns to your office 10 years later.
She, 38 years old, G2P1, presents with a new partner, who is 49 years old and
healthy.
They underwent IVF with PGD for the
22q11.2 deletion.
They are10 weeks pregnant with twins.
How do you counsel them?
Esther Friedrich, MD – November 2018 – Interregional Symposium
Exercise 3
They decline prenatal screening, but desire anatomy US screening.
Twin A appears healthy, twin B is noted to have an omphalocele on screening US.
She declines amniocentesis.
The pregnancy progresses, but twin B
shows accelerated growth and polyhydramnios and they are born at 33
weeks.
Esther Friedrich, MD – November 2018 – Interregional Symposium
Exercise 3
Twin B is diagnosed with Beckwith Wiedeman Syndrome after birth
The couple returns 5 years later for preconception counseling.
She is now 43 years old, he 52, and they are wondering about their reproductive
options.
How do you counsel them?