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Prenatal screening for genetic disorders: best current practice and what’s around the corner. June C Carroll MD CCFP FCFP Sydney G Frankfort Chair in FM Associate Professor and Research Scientist Department of Family & Community Medicine Mount Sinai Hospital, University of Toronto

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prenatal screening for genetic disorders best current practice and what s around the corner

Prenatal screening for genetic disorders: best current practice and what’s around the corner

June C Carroll MD CCFP FCFP

Sydney G Frankfort Chair in FM

Associate Professor and Research Scientist

Department of Family & Community Medicine

Mount Sinai Hospital, University of Toronto

OCFP 51st ASA, November 29, 2013

objectives
Objectives
  • Prenatal screening for genetic disorders
    • FTS/IPS/MSS
    • Non-invasive prenatal testing (NIPT)
    • Use of microarray for prenatal diagnosis
  • Ethnicity based screening
  • Consanguinity and genetics
factors affecting fts ips screening performance and why you need to record them on the requisition
Factors affecting FTS/IPS screening performance…and why you need to record them on the requisition

Gestational dating

FPR lowered by ~2% when GA estimated using scan

Maternal weight

Negative association between levels of maternal serum markers and maternal weight due to dilution effect produced by increased blood volume

Weight adjustment

increases DR by ~1% for a given FPR

reduces FPR by 0.2% for given DR

Ethnic origin

Adjusting tends to equalize the FPR among women of different ethnic groups

SOGC Guidelines 2011

factors affecting fts ips screening performance and why you need to record them on the requisition1
Factors affecting FTS/IPS screening performance…and why you need to record them on the requisition

Insulin-dependent diabetes mellitus

Some T2 markers are lower

Smoking

Affects risk calculations – indicate if any smoking during pregnancy (even at time of conception)

Assisted Reproduction

Maternal age used is age of donor or woman at time egg was harvested

IVF pregnancies have higher risk of false positive screen – correction factor used – so important to indicate

SOGC Guidelines 2011

prenatal genetic screening
Prenatal Genetic Screening

Maternal age

Practice of using solely maternal age at EDD to identify at-risk pregnancies should be abandoned

DR for DS: 44%, FPR 16%

Maternal age should not be used as a basis for recommending invasive testing when non-invasive PN screening is available

Modify age-related risk by multiple biochemical markers with or without first trimester u/s assessment of nuchal translucency

SOGC Guidelines 2011

use of ultrasound in screening for chromosomal anomalies
Use of Ultrasound in Screening for Chromosomal Anomalies

Detailed u/s at 18-20 weeks’ gestation

Most major fetal anatomic abnormalities will be detected

Majority of ONTD

Soft markers

Should not be used alone

Use to modify any a priori risk established by age or prior screening

In absence of soft markers and anomalies – reduction of risk of 0.5 can be applied – only in tertiary level scan centre

See 2007 SOGC Ultrasound Soft Marker Guideline

SOGC Guidelines 2011

prenatal screening with addition of non invasive prenatal testing nipt
Prenatal Screening with addition of Non-invasive Prenatal Testing (NIPT)

What is NIPT?

What is the evidence for NIPT?

What do the experts say?

What is current Ontario prenatal screening landscape?

what is non invasive prenatal testing nipt
What is Non-invasive Prenatal Testing (NIPT)?
  • Screening test to prenatally detect Down syndrome and other aneuploidies (extra or missing chromosomes)
    • trisomy 21, 18, 13
    • trisomy of sex chromosomes (XXX, XXY, XYY)
    • Turner syndrome (monosomy X)
    • triploidy (extra copy of all chromosomes)
slide10
NIPT

NIPT measures circulating cell free fetal DNA (ccffDNA) present in maternal blood (from trophoblast)

Comprises ~10% of DNA in maternal blood

Increases with gestational age

ccffDNA analysis determines if normal, higher, or lower than expected quantity of particular DNA sequences found on select chromosomes (13, 18, 21, X, Y)

Performed on maternal blood sample

As early as 9 weeks’ gestation

Dating u/s – viability, accurate GA, exclude multiples

what s the evidence for nipt
What’s the evidence for NIPT?
  • 7 studies of “high risk” women
  • High risk:
    • Screen positive
    • AMA (≥35 yrs)
    • Ultrasound findings
    • Family history indicating increased risk
      • Previous pregnancy with aneuploidy
what s the evidence for nipt1
What’s the evidence for NIPT?

Benn et al, Ultras Obstet Gynecol 2013, 42: 15-33

By far most accurate performance for T21/18

what s the evidence for nipt2
What’s the evidence for NIPT?

Benn et al, Ultras Obstet Gynceol 2013, 42: 15-33

  • 4 studies on unselected pregnancies
    • Most mixed risk, some after pos screen, AMA, fewer with neg or no screen
    • > 14,000 pregnancies total, largest (11,000 significant loss to follow up)
    • Similar performance
  • Not yet validated in low risk women, triplets or higher, pregnancies conceived with egg donation
what s the evidence for nipt3
What’s the evidence for NIPT?

Benn et al, Ultras Obstet Gynceol 2013, 42: 15-33

  • Failed results
    • 6.1% (0.8-9.9) untested for insufficient sample quality
    • 2% (436/22,222) no result after testing
    • Rarely happens with conventional screening
    • ccffDNA decreases with increased maternal BMI
summary of evidence for nipt
Summary of evidence for NIPT

Benn et al, Ultras Obstet Gynceol 2013, 42: 15-33

what do the experts say
What do the experts say?

American College of Obstetricians and Gynecologists 2012

Has been validated in industry sponsored studies on at risk populations

History of prior pregnancy with trisomy

Positive multiple marker test

Parental balanced Robertsonian translocation with increased risk of fetal trisomy 13/21

Maternal age >35

Fetal ultrasound findings with increased risk of aneuploidy

ACOG Committee Opinion: Dec 2012

what do the experts say1
What do the experts say?

Society of Obstetricians & Gynecologists of Canada 2013

Non-invasive prenatal testing using massive parallel sequencing of cell-free fetal DNA to test for trisomies 21, 18, and 13 should be an option available to women at increased risk in lieu of amniocentesis. Pretest counselling of these women should include a discussion of the limitations of non-invasive prenatal testing.

Genetics Ctte Technical Update JOGC: Feb 2013

what do the experts say2
What do the experts say?

Society of Obstetricians & Gynecologists of Canada 2013

No irrevocable obstetrical decision should be made in pregnancies with a positive non-invasive prenatal testing result without confirmatory invasive diagnostic testing.

Genetics Ctte Technical Update JOGC: Feb 2013

recommendation in ontario
Recommendation in Ontario

Offer all women prenatal screening using either FTS, IPS or MSS (SIPS or Quad)

IF screen +ve or at high risk for other reasons

Consider NIPT as secondary screen of higher sensitivity if she is willing to pay for the test

High risk:

Advanced maternal age

Previous aneuploidy pregnancy

Personal hx of sex chromosome aneuploidy (Turner mosaic, XXX)

Abnormal u/s

Pregnancy conceived via reproductive technologies

recommendation in ontario1
Recommendation in Ontario

NIPT is not a replacement for diagnostic PN testing

Positive NIPT should be confirmed by diagnostic testing: amnio or CVS

Expected benefit of NIPT: fewer women having diagnostic tests with associated risk of pregnancy loss

recommendation in ontario2
Recommendation in Ontario

If result is negative → reassuring

NIPT cannot:

Completely rule out aneuploidy

Detect chromosome differences other than aneuploidy of chromosomes 13, 18, 21, X and Y

Detect single gene conditions

Detect congenital anomalies

Still offer MSAFP and 18-20 wk ultrasound

recommendation in ontario3
Recommendation in Ontario

If result is positive:

Genetic counselling

Confirmation by diagnostic testing

No irrevocable obstetrical decisions should be made in pregnancies with abnormal NIPT results without confirmatory invasive testing (CVS or amnio) - SOGC

nipt in ontario
NIPT in Ontario

Increasing demand from women (who can pay)

Increasing uptake in most (urban) centres

3 separate companies, 3 separate technologies

No mechanism to evaluate centrally

Has it become mainstream now, become a “standard of care”? (? Only for high risk women)

Heading for 2 tiered prenatal screening

Costs between $795 and $1200

8-10 days for result

where does nipt fit with respect to the 11 to 14 wk scan
Where does NIPT fit with respect to the 11 to 14 wk scan?
  • 11 to 14 week scan has value to pregnancy care
    • NT may shift in importance (importance to other chromosomal, genetic and structural disorders)
    • Accurate dating/establishment of live fetus
    • Multiples/chorionicity affects management
    • Detects structural abnormalities
nipt and counselling
NIPT and counselling
  • Likely primary providers will not have time/expertise to counsel in detail
  • Refer to genetic counselling if your centre provides that service (significant impact on counselling demands)
  • Company websites:
    • Panorama™ by Lifelabs
    • Harmony™ by Ariosa
    • Verifi™ by Verinata Health (Medcan)
chromosomal microarray cma
Chromosomal Microarray (CMA)

Test DNA from patient labeled Green

Reference DNA from control labeled Red

Denature the DNA (separate the strands) and Hybridize to slide

Areas of loss (deletion)

Glass microarray slide

Computer scans and analyzes signal outputs

Area of gain (duplication)

CMA is a technology used to determine if there are small extra (microduplication) or missing (microdeletion) pieces of genetic information. These gains and losses are called copy number variants (CNVs). A CNV can be: of no medical consequence; pathogenic resulting in physical and/or intellectual consequences; or protective against disease (e.g. HIV infection).

microarray for prenatal diagnosis
Microarray for Prenatal Diagnosis

Wapner NEJM 2012, Callaway Prenatal Dx 2013

  • Microarray can detect submicroscopic copy number changes that are associated with clinically significant outcomes
  • Systematic review to calculate utility of PN microarray in presence of normal conventional karyotype
    • 12,362 pregnancies
      • 2.4% overall had copy number changes with associated clinical significance
      • 6.5% if ascertained because of abnormal ultrasound
      • 1.0% if increased maternal age
      • 1.1% for other reasons (parental anxiety, abnormal MSS)
microarray for pn diagnosis
Microarray for PN diagnosis

Wapner NEJM 2012

  • Microarray generally detects all aneuploides and unbalanced translocations identified on karyotyping
    • Does not identify balanced translocations/triploidy
microarray for pn diagnosis1
Microarray for PN diagnosis

Wapner NEJM 2012, Callaway Prenatal Dx 2013

  • Summary
    • Consider when doing invasive test like CVS or amnio
    • Added diagnostic value of microarray especially when karyotype gives normal chromosome result
    • Genetic consult will assist with which test is most appropriate depending on clinical presentation
      • karyotype, microarray or both
    • Challenges:
      • Variants of unknown significance
      • Incidental findings
    • Future:
      • Next generation sequencing, whole genome sequencing
slide33
Ethnicity based screening: Carrier testing for persons of French Canadian background- Charlevoix/Saguenay-Lac-Saint-Jean area

Screen all Fr Can/Cajun descent for TSD – take a FH/ refer from regions above

consanguinity
Consanguinity

Deeply rooted cultural trend among 1/5 of world population

Mostly residing in Middle East, West Asia, North Africa and emigrants from these communities

Intra-familial unions account for 20-15+% of all marriages

First cousins 1/3 of all marriages

Def’n: union between 2 people who are related as second cousins (5th degree relatives) or closer

First cousins, first cousins once removed, second cousins

Hamamy J Community Genetics 2012

consanguinity1
Consanguinity

Mainly cultural reasons for consanguineous marriages

Strategy to preserve transmission of cultural values and continuity

Maintenance of familial structure and property

Financial advantage relating to dowry, keeping property within family

Sometimes thought to be more stable unions

Same social relationships before and after marriage

consanguinity2
Consanguinity

Genetic Risk: first cousin marriages compared to non-consanguineous marriages

Fertility rate slightly higher

Miscarriage rate not different

Stillbirths and infant mortality rates slightly higher

Congenital anomalies 2-3% higher than background population risk (2-3%)

Increased likelihood of autosomal recessive conditions

Increased risk for almost all multifactorial birth defects including congenital heart defects, clefting, club feet, etc

Complex diseases – really not known – could be significant if high susceptibility gene present in family

Hamamy J Community Genet 2012

consanguinity3
Consanguinity

Management

Premarital/preconception counselling

For carrier status

May change marriage plans

3 to 4 generation FH

Appropriate testing based on FH and ethnic background

i.e. screen for common autosomal recessive conditions in pop and community

Refer to genetics if FH points to presence of genetic disorder

consanguinity4
Consanguinity

Concerns

Fear of stigmatization

Belief that inherited disorders can only arise through cousin marriages on paternal side – specifically inquire re shared biologic relationships on mother’s side

Need to balance risks and benefits

prenatal screening summary
Prenatal Screening Summary

Offer all pregnant women, regardless of age, PN screening for fetal aneuploidy (trisomy 13, 18, 21) through FTS, IPS, SIPS or Quad screening

+ second trimester ultrasound for dating, assessment of fetal anatomy and detection of multiples

Maternal age should not be used as a basis for recommending invasive testing when non-invasive PN screening is available

Consider offering NIPT to high risk women or following a positive PN screen for aneuploidy

prenatal screening summary1
Prenatal Screening Summary

Take a FH to identify familial and/or ethnically related disorders and screen accordingly

Consider consanguinity and screen and test accordingly

Refer or consult genetics when in doubt

useful genetics resources
Useful Genetics Resources

GEC-KO website: Genetics Education Website

www.gecko-cegco.ca

NIPT fact sheets:

http://www.mountsinai.on.ca/care/pdmg/NIPT%20info%20sheet%20for%20parents%2029_11_2012.pdf

http://www.mountsinai.on.ca/care/pdmg/NIPT%20info%20sheet%20for%20For%20Healthcare%20Providers%2029_11_2012.pdf

Prenatal Screening Ontario Website

http://www.prenatalscreeningontario.ca/

morrison@cheo.on.ca, jcarroll@mtsinai.on.ca

Thanks to Shawna Morrison, GEC-KO program manager for assistance with this presentation

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