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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

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UPDATE ON PERINATAL GENETICS

Mary E. Norton MD Professor, Obstetrics, Gynecology, and Reproductive Sciences University of California, San Francisco 2019 UCSF Obstetrics and Gynecology Update

Disclosure

  • Research support: Natera
  • Consultant, Scientific Advisory Board: Invitae

Gartner Hype Cycle

Chromosomal microarray Cell free DNA screening Exome sequencing

Genomic variation

Down syndrome 22q deletion syndrome Cystic fibrosis

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The Prenatal Testing Paradigm

Down syndrome No Yes Terminate pregnancy No Yes

20 40 60 80 100 120

Detection rate of prenatal screening for Down syndrome has improved over time

Detection Rate (%)

1997

Analysis of cell free DNA

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DR: 99.2% (98.5 - 99.6) FPR: 0.09% (0.05 - 0.14)

False Positive Rate: 1/2500

cfDNA screening for T21: meta-analysis

(Gil et al, Ultrasound Obstet Gynecol, 2017)

Detection Rate: 99.7%

High Risk, Low Risk, and Positive Predictive Value

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%)

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Risk Group Positive predictive value Entire cohort (mean age 30.7 yrs 81% Maternal age <35 yo 76% Low risk serum FTS (<1/270) 50%

PPV Calculator: www.perinatalquality.org

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DOWN SYNDROME!!

“How did this happen? I had the non-invasive amnio…”

Spectrum of Congenital Disease

Structural Malformations

Autosomal recessive Autosomal dominant X-linked Chromosomal/ karyotype

Conditions found by microarray

  • 1/300

pregnancies

  • 20% of

infant deaths

Half of these are Down syndrome

Copy number variants

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Spectrum of Congenital Disease

Structural Malformations

Autosomal recessive Autosomal dominant X-linked Chromosomal/ karyotype

Chromosomal microarray

  • Gene

sequencing

  • Carrier

screening

  • Cell free DNA
  • Karyotype

Copy number variants

Ultrasound

Chromosomal microarray

  • “Lab-on-a-chip”
  • Tests for thousands
  • f copy number

variants at the same time

  • Microdeletions and

microduplications

Microdeletions are genomic imbalances detected by microarray but not karyotype

Miller et al, 2010, AJHG

Russell Silver syndrome: Small, asymmetric Mild learning disabilities Prader- Willi: Hypotonia, significant learning disabilities,

  • besity

Angelman syndrome: Severe intellectual disability and speech impairment

Some Microdeletion Syndromes Ch 7 Ch 15 Ch 5

Cri du chat syndrome: Poor feeding and growth, microcephaly, severe learning difficulties

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10/17/2019 7 Rate of abnormalities by maternal age

Increasing maternal age 

(Microarray abnormalities) 35 yo

Chromosomal Microarray (CMA) for Prenatal Diagnosis

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%

Cell free DNA: Expanded panels

  • Trisomies 9, 16 and 22
  • Rarely seen in viable pregnancies except as mosaics
  • Common causes of confined placental mosaicism
  • Much more common in CVS samples than amniocentesis
  • Even complete trisomy in the placenta often

associated with a normal fetus

  • Selected microdeletions
  • 22q, 1q36, 5p-, 4p-, 15q11-13
  • Also 8q-, 11q-
  • MaterniTGenome

Microdeletion syndromes tested by cfDNA expanded panels

Syndrome Frequency Features 22q11.2 (DiGeorge) 1/4,000 Varies: cardiac, palatal, immune, intellectual disability 1q36 1/10,000 Severe intellectual disability (ID), +/-

  • bvious structural anomalies

Angelman 1/20,000 Severe ID, seizures, speech delay Prader-Willi 1/30,000 Obesity, ID, behavioral problems Cri-du-chat 1/50,000 Microcephaly, ID, +/- CHD Wolf-Hirshhorn 1/50,000 ID, seizures, +/- CL/CP Total 1/2500

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Diagnostic confirmation for cfDNA for microdeletions

Deletion Total # of cases # confirmed Positive Predictive Value

1p 21 1 4.8% 4p 6 1 16.7% 5p 45 6 13.3% 15q 80 5 6.3% 22q 183 12 6.6% Total 335 25 7.4%

Schwartz et al, Prenatal Diagn, 2018

Chromosomal microarray vs cfDNA: Bottom line

  • Diagnostic testing with chromosomal

microarray is the best test for pregnant women who want as much information as possible about their fetus.

  • Women should be counseled about the chance
  • f finding a variant of uncertain significance
  • Cell free DNA can detect only a tiny number of

the total microdeletions

MaterniTGenome: “Non-invasive Genome”

Screen positive rate: 5.4%

December, 2017

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Cell free DNA and cancer

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cfDNA screening  Trisomy 13, 18, 21  Sex chromosomes  +/- microdeletions  Maternal cancer  Maternal CNV  Maternal sex chromosomal aneuploidy Traditional screening

 Trisomy 18, 21, +/-13  Spina bifida and ventral wall defects (MSAFP)  Other chromosomal  Early dx fetal anomalies, including cardiac (NT)  Adverse obstetric

  • utcomes

 Preeclampsia, PTB, FGR

Spectrum of Congenital Disease

Structural Malformations

Autosomal recessive Autosomal dominant X-linked Chromosomal/ karyotype

Chromosomal microarray

  • Gene

sequencing

  • Carrier

screening

  • Cell free DNA
  • Amniocentesis

Copy number variants

Ultrasound

Newborn screening Carrier screening NEWBORN

Screening for Affected

PRENATAL

Screening for Carriers

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)

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Expanded (Universal) Carrier Screening Expanded (Universal) Carrier Screening

Utilization of new technologies to identify carriers of multiple genetic conditions simultaneously

The future: Whole genome sequencing The future: Whole genome sequencing

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10/17/2019 12 Whole Genome and Exome Sequencing

  • Whole Genome Sequencing
  • Obtaining the complete sequence of all 3 billion

base pairs of DNA in any individual

  • Exome Sequencing
  • Obtaining the complete sequence of the ~2% of

the genome containing the exons that encode proteins

Separating the Wheat from the Chaff

What is a “normal” genome?

“The Thousand Dollar Genome” “The Ten Thousand Dollar Interpretation”

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What is exome sequencing?

exome sequencing is a technique for sequencing all of the protein-coding genes in a genome (known as the exome).

A genome is like watching the game from beginning to end An exome is like reading the highlights

N=234  10% diagnostic yield

Exome sequencing in fetal anomalies

Lancet 2019

N=596  8.5% diagnostic yield

Clinical Sequencing Evidence Generating Research Consortium: Is There Clinical Benefit?

Institution Study focus Baylor Pediatric cancer Hudson Alpha Sequencing newborns Kaiser Cancer predisposition Mt Sinai Pediatric undiagnosed disorders UCSF Pediatric and prenatal disorders UNC Adult and pediatric disorders UW Coordinating center

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6 4 3 2 48 3 63 10 20 30 40 50 60 70

Definitive Positive Probable Positive Inconclusive Investigational Findings Negative Secondary Findings Total Results Returned

Prenatal WES Results

10/63 = 16% 5/10 (50%)  nonimmune hydrops

41 y.o. G1P0 at 32 weeks gestation Fetal MRI

Markedly abnormal

  • Global cerebral volume loss
  • Markedly diminished white matter volume

and germinolytic cysts in the ganglionic eminences

  • Appearance destructive: patient ID specialist

Fetal evaluation

  • Normal microarray
  • Meta-genomic analysis: no pathogens identified
  • Whole exome sequencing:
  • De novo heterozygous missense variant in TUBB2A
  • TUBB2A gene encodes beta tubulin, a subunit of

microtubules.

  • Variants in this gene are associated with complex

cortical dysplasia with other brain malformations (MIM#615763), an emerging autosomal dominant syndrome characterized by seizures, brain abnormalities and developmental delay 53 54 55 56

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Prenatal whole exome sequencing

  • Broad range of diagnostic yield: 6.2-80%
  • Inclusion criteria
  • Analysis of trios
  • 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
  • Need improved pipelines for prenatal sequencing

What is the future? Conclusions

  • 3 million women undergo prenatal genetic testing

each year

  • Genetic testing can identify far more than Down

syndrome

  • There are many reasons for undergoing prenatal

testing beyond pregnancy termination

  • Rapid uptake of cfDNA screening suggests that

women will continue to desire the next best prenatal genetic test

  • The question is not whether prenatal noninvasive

genome sequencing should be performed, but how to optimally implement

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Thank you!

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