Update on Perinatal Genetics

Mary E Norton, MD

Department of Obstetrics, Gynecology, and Reproductive Sciences

University of California, San Francisco

61st ANNUAL OB/GYN UPDATE

Park City UT

February 2020

Disclosures

• Research funding from Natera• Consultant to Invitae

Gartner Hype Cycle

Chromosomal microarray

Cell free DNA screening

Expanded carrier screening

Genomic variationDown syndrome

22q deletion syndrome

Cystic fibrosis

Availability of Genetic Tests

Most of these are for inherited disorders

"an emerging approach for disease

treatment and prevention that takes

into account individual variability

in genes, environment, and lifestyle for each

person.”

Precision Medicine

Precision Medicine

Genetics/Genomics and Women’s Health

Women’s Health

• Screening for health risk• Cancer• Other disorders

• Reproductive risk• Carrier screening• Prenatal testing

Direct to Consumer Genetic Testing

Case presentation

Patient produces 23andMe document

Case presentation

1

23andMe Traits Reports • Asparagus Odor

Detection• Back Hair (available for

men only)• Bald Spot (available for

men only)• Bitter Taste Perception• Cheek Dimples• Cleft Chin• Earlobe Type• Earwax Type• Eye Color• Finger Length Ratio

• Freckles• Hair Curliness• Light or Dark Hair• Male Hair Loss (available

for men only)• Newborn Hair Amount• Photic Sneeze Reflex• Red Hair• Skin Pigmentation• Sweet Taste Preference• Toe Length Ratio• Unibrow• Widow's Peak

23andMe Wellness Reports• Alcohol Flush Reaction• Caffeine Consumption• Deep Sleep• Lactose Intolerance• Muscle Composition• Saturated Fat and Weight• Sleep Movement

Case presentation

Case presentation

BRCA1/2 23andMe testing

BRCA1/2 23andMe testing

Direct to Consumer Genetic Testing

Uses/ Benefits• Determine ancestry• Recruit to research

studies• Assess health risks• Entertainment

Challenges/Risks• Complex to interpret• Not clinically validated• Privacy concerns

• Unexpected findings• Relatives• Law enforcement

• “The test is not a substitute for visits to a healthcare professional for recommended screenings or appropriate follow-up. Results should be confirmed in a clinical setting before taking any medical action. “

Direct to Consumer Genetic Testing

Is DTC testing accurate?

• From 23andMe: “The raw data provided by 23andMe has undergone a general quality review; however, only a subset of markers have been individually validated for accuracy. The data from 23andMe’s Browse Raw Data feature is suitable only for informational use and not for medical, diagnostic or other use. Consult with a healthcare professional before making any major lifestyle changes.”

Direct to Consumer Genetic Testing

• High FP rate attributed to testing methodologies• DTC labs use SNP genotyping (coverage at only specific

predetermined sites) vs. full-gene sequencing with del/dup analysis

• Probe coverage varies even between DTC companies

• Clinical confirmatory testing is indicated for any raw data variant This is not a substitute for clinical testing!

Expanded (Universal) Carrier Screening

Expanded (Universal) Carrier Screening

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

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 numbervariants

Ultrasound

Recessive inheritance

Unaffected carriers Affected

Recessive inheritance

Unaffected carriers Affected

What is the purpose of prenatal carrier screening?

What is the purpose of newborn screening?

Newborn screening

Carrier screening

NEWBORN

Screening for Affected

PRENATAL

Screening for Carriers

Wilson and Junger: Criteria for screening for disease

• A good test is available• The disorder is common• The disorder is severe• There is an intervention• Testing is voluntary and patients give informed

consent

History of Prenatal Carrier Screening1. Hemoglobinopathies 1970’s2. Tay Sachs disease 19713. Canavan disease 19984. Cystic fibrosis 20015. Familial dysautonomia 20046. 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)

Traditional Carrier Screening• Focus on ancestry and family history• Small number of diseases

• High frequency in a certain population• Severe morbidity or mortality• Fetal, neonatal or early childhood onset• Well-defined phenotype

Sickle cell disease Tay-Sachs disease

Ethnicity Based Screening

Ashkenazi Jews Tay Sachs disease, Canavan disease,

cystic fibrosis, familial dysautonomia

Louisiana Cajun, Tay Sachs diseaseFr Canadian

Caucasians Cystic fibrosisAfricans, African Sickle cell anemia, beta

Americans thalassemiaSoutheast Asians Alpha thalassemiaMediterraneans Beta thalassemia

ACOG 2017 Updated Screening Recommendations

• Screening should be offered to all women before or during pregnancy for:

• Cystic fibrosis• Spinal muscular atrophy

• MCV should be offered to all women who are currently pregnant

• To those at risk for hemoglobinopathies, Hbelectrophoresis should be offered (African, Mediterranean, Middle Eastern, SE Asian, West Indian) or if MCV is low

ACOG 2017 Updated Screening Recommendations

It is reasonable to do:• Ethnicity based screening• Pan-ethnic screening

• Same tests are offered to everyone

• Expanded carrier screening

Multiplex Panel Screening:Expanded Carrier Screening

• Multiplex screening now allows testing for many (>100) disorders at once

• This is relatively inexpensive (~$350)

• Should it be offered to everyone?

Is More Better?

• What are these additional conditions?• What is the process for adding new conditions?• Is the test accurate?• How often does the test find something?• What happens then?

Newborn vs prenatal screening

Disorder is important test is developed and introduced

Technology is developed test is introduced

What is on expanded panels and how are disorders chosen?

Disorders should be:• Severe• Common• Have a well-described natural history and

phenotype• Have a high detection rate

What criteria are required by laboratories before adding gene variants to panels?

Achromatopsia

• Decreased visual acuity, nystagmus• Increased light sensitivity• Decreased color discrimination

• Non-progressive• Does not lead to blindness• No other organ system affected

• Should this be on panels?

Condition 1/α1AT deficiency 13

Cystic fibrosis 28DFNB1 43SMA 57Fam Mediterranean Fever 64SLO 68SS/ β-thal 70Gaucher disease 77Factor XI deficiency 92Achromatopsia 98

• 23,453 patients screened for 96 conditions

• Mild conditions excluded:hemochromatosis (HFE)MTHFRothers

Lazarin GA, et.al.. Genetics in Med 2012.

Expanded Carrier Screening: The Wild West

Gene variants

What criteria are required by laboratories before adding variants to panels?

Test is available

Optimal criteria for carrier screening: ACMG and ACOG

• Good test is available• Detection rate ≥ 70%

• Carrier frequency is high• At least 1 in 100

• Exclusions:• Adult onset• Poorly studied• Prevalence unknown• Incomplete penetrance• Mild phenotype

• Evaluated commercially available panels• 27% of included disorders meet criteria per ACMG

and ACOG

How Often Do Tests Find Something?

What Then?

24-45% will have something• Explain to the patient• Test the partner (he might not have insurance)• He will often have something else

• If low detection rate on original panel, do gene sequencing• Explain all this to the patient

A real patient story

• Patient reports that she carries SMA• Partner has expanded carrier screening through panel covered by

his insuranceCarries Fanconi Anemia, group A

• Patient undergoes expanded carrier screening with panel covered by her insurance She carries Pompe disease but was not tested for Fanconi group A, just

group C (updated panel)• They are frustrated and seek a second opinion• He undergoes gene sequencing for Pompe and she has

sequencing for Fanconi group A• All he really needed was testing for SMA

Another patient story

• Patient and partner had expanded carrier screening during first pregnancy (in NY)

• Both carried a variant for Zellweger disease• Life-threatening metabolic disorder• Usually neonatal death

• Had prenatal diagnosis: fetus carrier

Delayed pregnancy for THREE years

• Saw GC for pre-conception counseling• Planning for preimplantation genetic testing• GC was having a slow day….

Results

Results (Page 2 of report, fine print)

Researched this variant

• ClinVar (public database)• 2 labs: pathogenic or likely pathogenic• 1 benign• 1 VUS (variant of uncertain significance)

• Gnomad (another genome database)• 8 individuals who were homozygous and presumably

normal

• PubMed• Called a researcher, who said that variant should be

reclassified as benign

The bottom line:• Genetics is complicated!• But it is the future

Questions?