prenatal genetic screening dbiagnosis hamamy 2010

8/11/2019 Prenatal Genetic Screening DBiagnosis Hamamy 2010

1/27

Prenatal genetic screening and

diagnosis

Hanan Hamamy

Department of Genetic Medicine and DevelopmentGeneva University Hospital

Training Course in Sexual and Reproductive Health ResearchGeneva 2010


2/27

While it is never easy for a couple to decide topursue prenatal diagnosis because of thepossibility of subsequently having to considertermination of pregnancy, prenatal diagnosis isan option that is chosen by many couples at highrisk of having a child with a serious congenitaldisorder.


3/27

Methods used for prenatal diagnosis of congenitaldisorders

Invasive Non-invasive Preimplantation

Amniocentesis

Chorion villus

biopsy

Fetal blood,other tissues

Ultrasonography

Maternal serum

markers

Fetal cell samplingfrom maternal blood


4/27

Prenatal genetic screening

For most women, prenatal genetic screening involvesa blood test for maternal serum markers and a specialultrasound done in the first trimester.

Abnormal results could point to the possibility thatthe fetus has :

1. Down syndrome2. Other chromosomal abnormalities such as Trisomy 18 and Turner syndrome3. Open neural tube defect (ONTD)

4. Other conditions


5/27

Neural tube defect

Spina bifida indicates a defect in the closure of the vertebralcolumn leading to protrusion of the meninges/spinal cord.Severe conditions lead to lower limb paralysis and incontinence


6/27

the observation that increased nuchaltranslucency (NT) is seen in fetuses who aresubsequently born with Down syndrome, hasresulted in the introduction of measurementsof nuchal pad thickness in the first trimesteras a screening test for Down syndrome


7/27

Ultrasound offers a valuable means of prenataldiagnosis. It can be used not only for obstetricindications, such as placental localization and thediagnosis of multiple pregnancies, but also for theprenatal diagnosis of structural abnormalities thatare not associated with known chromosomal,biochemical or molecular defects. Ultrasound isparticularly valuable because it is non-invasive andconveys no known risk to the fetus or to the mother.

It does, however, require specialized expensiveequipment and a skilled and experienced operator


8/27

Detailed 'fetal anomaly' scanning is beingoffered routinely to all pregnant women ataround 18 weeks gestation as a screeningprocedure for structural abnormalities such ascardiac and other congenital malformations


9/27

First trimester risk assessment using the doubletest (pregnancy-associated plasma protein A(PAPP-A) and free beta-human chorionicgonadotropin (HcG) and nuchal translucencythickness in combination with maternal age hasbeen shown to be very efficient giving adetection rate of 90% for Down syndrome andfor a 5% false-positive rate


10/27

A screening test does not give a yes or noanswer but identifies increased risk for certaindisorders so that definitive diagnostic testscan be offered.

If the risk is considered high, then diagnostictests could be done by obtaining fetal tissueseither through chorion villus sampling or

amniocentesis.


11/27

Progression of Prenatal screening

maternal serum markersUltrasound

Abnormal results

CVSamniocentesis

Abnormal results

Termination


12/27

A fundamental difference between prenatal and othertypes of screening is that when prenatal screening leadsto the diagnosis of an abnormality in the fetus there isfrequently no treatment available before birth. Women

are left with the choice between continuing thepregnancy knowing the infant will be born with thecondition identified or abortion to prevent the birth ofan affected child


13/27


14/27

Advanced maternal age, usually defined as 35years or more, used to be the most commonindication for invasive prenatal diagnosis. Inmany countries, this indication has beenreplaced by an individualised risk assessmentfor Downs syndrome based on maternal age,gestational age, and a combination of ultrasonicand biochemical markers.


15/27

Amniocentesis

Done around the 16th weekof gestation

Aspiration of 20 ml of

amniotic fluid through theabdominal wall underultrasound guidance

0.5-1% risk of miscarriage


16/27

Chorion villus sampling

Usually performed at 11-12 weeks gestation

Transcervical aspiration ofchorionic villi underultrasound guidance

Around 1% risk ofmiscarriage


17/27

Fetal risks following amniocentecis

The earlier the amniocentesis is performed,the higher the risk of amniotic fluid leakageand the higher the risk for foot deformities.

Therefore amniocentesis should not beperformed before 15 weeks gestation.


18/27

Fetal risks following Chorion villussampling

CVS should not be performed before 10 weeksdue to the risk of limb reduction defects.

Experienced operators have a higher successrate and a lower complication rate.


19/27

Parents request prenatal diagnosis because they cannothave another affected child

Reasons forRequestingPrenataltesting

Poor financialresources of

the family

EmotionalDifficulty

to have another

affected child

Unfair to giveBirth to child

that will suffer

Scarce andunaffordable

specialised care

& rehabilitation


20/27

Problems of the mother

Feelings of guilt andfear of future

Familyblames her

Husband nothelpful

Taking care ofother children


21/27

Following the prenatal diagnosis of afetal congenital disorder

The couple should be counseled by a geneticcounselor to inform them of the test resultsand the risks to the fetus.

The couple should take an informed decisionabout termination or continuation of pregnancy

Autonomy of decision is crucial. The ethical, legal, and religious issues should be

respected.


22/27

Selective termination of pregnancy whenfetus is affected???

How can congenital disorders be categorized???

1. Severity of disease

2. Survival3. Impact on family4. Impact on affected5. Impact on society and government


23/27

Preimplantation Genetic Diagnosis(PGD)

Preimplantation Genetic Diagnosis (PGD) uses in vitrofertilisation (IVF) to create embryos. Tests one or two cells from each embryo for a

specific genetic abnormality.

Identifies unaffected embryos for transfer to theuterus. The approach through PGD assists couples at risk of

an inherited disorder to avoid the birth of anaffected child without going through selectivepregnancy termination.

Please refer to the presentation of Thalassemias

by Dr Marina Kleanthos for further details on PGD


24/27

Indications for PGD

1. To detect chromosomal disorders by fluorescence in situhybridisation (FISH).

2. To determine the sex of the embryo for sex linked disorderswhere the specific genetic defect at a molecular level isunknown, highly variable, or unsuitable for testing on singlecells for example Duchenne muscular dystrophy.

3. To identify single gene defects such as cystic fibrosis, wherethe molecular abnormality is testable with moleculartechniques after polymerase chain reaction (PCR) amplificationof DNA extracted from single cells.

Please refer to the presentat ion of Thalassemias

by Dr Marina Kleanth os fo r fur ther detai ls on PGD


25/27

Please refer to the presentation ofThalassemias by Dr Marina Kleanthos forfurther details on PGDhttp://www.gfmer.ch/SRH-Course-2010/course-files/Thalassemia-Kleanthous-2010.htm
http://www.gfmer.ch/SRH-Course-2010/course-files/Thalassemia-Kleanthous-2010.htmhttp://www.gfmer.ch/SRH-Course-2010/course-files/Thalassemia-Kleanthous-2010.htmhttp://www.gfmer.ch/SRH-Course-2010/course-files/Thalassemia-Kleanthous-2010.htmhttp://www.gfmer.ch/SRH-Course-2010/course-files/Thalassemia-Kleanthous-2010.htmhttp://www.gfmer.ch/SRH-Course-2010/course-files/Thalassemia-Kleanthous-2010.htmhttp://www.gfmer.ch/SRH-Course-2010/course-files/Thalassemia-Kleanthous-2010.htmhttp://www.gfmer.ch/SRH-Course-2010/course-files/Thalassemia-Kleanthous-2010.htmhttp://www.gfmer.ch/SRH-Course-2010/course-files/Thalassemia-Kleanthous-2010.htmhttp://www.gfmer.ch/SRH-Course-2010/course-files/Thalassemia-Kleanthous-2010.htmhttp://www.gfmer.ch/SRH-Course-2010/course-files/Thalassemia-Kleanthous-2010.htmhttp://www.gfmer.ch/SRH-Course-2010/course-files/Thalassemia-Kleanthous-2010.htmhttp://www.gfmer.ch/SRH-Course-2010/course-files/Thalassemia-Kleanthous-2010.htmhttp://www.gfmer.ch/SRH-Course-2010/course-files/Thalassemia-Kleanthous-2010.htmhttp://www.gfmer.ch/SRH-Course-2010/course-files/Thalassemia-Kleanthous-2010.htm


26/27

Things to keep in mind*:

Informed choice - Before ordering the test,discuss benefits, risks and limitations.

Autonomy - The patient should choose whether

to have prenatal screening. What prenatal screening options are available inyour area?

What option is most suitable for your patient? Which test will provide the optimal care

for your patient? A screening test is not diagnostic.

*Reference Guide for Health Care ProvidersPrenatal Screening Tests for the Detection of:Down Syndrome, Trisomy 18 and Open Neural Tube Defectshttp://www.mountsinai.on.ca/care/family-medicine-genetics-program/resources/Provider%20Mongraph%2020070930%20FINAL_837629127.pdf


27/27

Prospects for the role of prenataldiagnosis in the future

Prenatal diagnosis can be followed by intrauterine orneonatal surgery for the correction of certaincongenital anomalies such as cardiac and renal defects.

In utero gene therapy could become a practical

therapeutic option in the future for the treatment ofserious monogenetic diseases.

Prenatal diagnosis with in-utero transplantation offersthe potential to treat a large number of diseases bytransplantation of healthy cells into a fetus with a birthdefect.

prenatal genetic screening dbiagnosis hamamy 2010

Documents