Update on Perinatal Genetics - 61st ANNUAL OB/GYN UPDATE Mary E Norton, MD Department of Obstetrics, Gynecology, and Reproductive Sciences ...
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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
Cell free DNA screening
Chromosomal microarray
Expanded
carrier
screening
Genomic variation
Down 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
123andMe Traits Reports
• Asparagus Odor • Freckles
Detection • Hair Curliness
• Back Hair (available for • Light or Dark Hair
men only)
• Male Hair Loss (available
• Bald Spot (available for
men only) for men only)
• Bitter Taste Perception • Newborn Hair Amount
• Cheek Dimples • Photic Sneeze Reflex
• Cleft Chin • Red Hair
• Earlobe Type • Skin Pigmentation
• Earwax Type • Sweet Taste Preference
• Eye Color • Toe Length Ratio
• Finger Length Ratio • Unibrow
• Widow's Peak23andMe 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 Challenges/Risks
• Determine ancestry • Complex to interpret
• Recruit to research • Not clinically validated
studies • Privacy concerns
• Assess health risks • Unexpected findings
• Entertainment • Relatives
• Law enforcementDirect to Consumer Genetic Testing • “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. “
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 simultaneouslySpectrum of Congenital Disease
Chromosomal Autosomal recessive • Gene
microarray Autosomal dominant sequencing
X-linked • Carrier
screening
Copy number Chromosomal/
karyotype
variants
• Cell free DNA
Structural • Amniocentesis
Malformations
UltrasoundRecessive inheritance
Unaffected carriers AffectedRecessive inheritance
Unaffected carriers AffectedWhat is the purpose of prenatal carrier screening?
What is the purpose of newborn screening?
Screening for Screening for
Carriers Affected
PRENATAL NEWBORN
Carrier Newborn
screening screeningWilson 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 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)
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 disease
Fr Canadian
Caucasians Cystic fibrosis
Africans, African Sickle cell anemia, beta
Americans thalassemia
Southeast Asians Alpha thalassemia
Mediterraneans Beta thalassemiaACOG 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, Hb
electrophoresis should be offered (African,
Mediterranean, Middle Eastern, SE Asian, West
Indian) or if MCV is lowACOG 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 introducedWhat 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?
• 23,453 patients screened Condition 1/
for 96 conditions α1AT deficiency 13
• Mild conditions excluded:
hemochromatosis (HFE) Cystic fibrosis 28
MTHFR
DFNB1 43
others
SMA 57
Fam Mediterranean Fever 64
SLO 68
SS/ β-thal 70
Gaucher disease 77
Factor XI deficiency 92
Lazarin GA, et.al.. Genetics in Med Achromatopsia 98
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 patientA real patient story
• Patient reports that she carries SMA
• Partner has expanded carrier screening through panel covered by
his insurance
Carries 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 SMAAnother 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 benignThe bottom line: • Genetics is complicated! • But it is the future
Questions?
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