Genetic counselling and Prenatal /Antenatal diagnosis

1. Genetic Counselling &
Prenatal Diagnosis
Dr. Dilip Choudhary
Department of Pediatrics,
Mata Chanan Devi Hospital, New Delhi
1 11/03/2016

2. Genetic Counselling
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3. Learning Objectives-
O 1. What is genetic counselling?
O 2. Why it is needed?
O 3. What are the clinical situations (indications)
where it is important?
O 4. Types of genetic counselling
O 5. What are the steps of genetic counselling?
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4. Introduction:
O Genetic counselling is communicative process which
deals with human problems associated with occurrence
and or recurrence of a genetic disorder in a family.
O An individual who seek genetic counselling is known as
a consultand.
O Counsellor is expected to present information in a
natural, nondirective manner and to provide support to
the individual and family to cope with decisions that are
made.
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5. This involves an attempt by counsellor to help the
consultand to:
 Understand the medical facts including diagnosis,
probable course of disorder and available
management.
 Understand the mode of inheritance of the disorder
and the risk of developing and/or transmitting it.
 Understand the alternatives for dealing with the risk
of recurrence.
 Choose the course of action which is appropriate for
them.
 Make the best possible adjustment to the disorder in
an affected family member and or to the risk of
recurrence of the disorder.
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6. Purpose of genetic counselling
 Provide concrete, accurate information about inherited
disorders.
 Reassure people who are concerned that their child may
inherit a particular disorder that the disorder will not
occur.
 Allow people who are affected by inherited disease to
make informed choice about future reproduction.
 Educate people about inherited disorder and the process of
inheritance.
 Offer support by skilled health care professionals to
people who are affected by genetic disorders.
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7. Indications
1. Advanced parental age:-
Maternal age ≥35 yrs
Paternal age ≥50 yrs
2. Previous child with or family H/O:-
Congenital anomaly
Dysmorphism
Intellectual disability
Developmental delay
Isolated birth defect
Metabolic disorder
Chromosomal abnormality
Myopathy/ Neuropathy
Ambiguous genitalia
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8. 3.Adult onset genetic disorder (presymptomatic testing):-
Cancer
4.Consanguinity
5.Teratogen exposure
6.Repeated pregnancy loss or infertility
7.Pregnancy screening abnormality
Maternal serum α-feto protein
Maternal triple or quad test
Fetal ultrasonography
Fetal karyotype
8.Heterozygote screening based on ethnic risk
Sickle cell anemia
Tay- sachs, Canavan, Gaucher disease
Thalassemia
9.Follow up to abnormal neonatal genetic testing
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9. Types of Genetic Counselling
Two types of genetic counselling:
(A) Prospective genetic counselling:
• This allows for the true prevention of disease.
• This requires to identify heterozygous individuals for
any particular defect by screening.
• Explaining to them the risk of their having affected
children if they marry another heterozygote for the
same gene.
• If heterozygous marriage can be prevented or
reduced, the prospects of giving birth to affected
children will diminish.
• Ex: Sickle cell anaemia
Thalassemia
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10. (B) Retrospective genetic counselling:
• Most genetic counseling at present is retrospective,
(the hereditary disorder has already occurred within
the family).
• Ex. Mental retardation
Psychiatric illness
Inborn errors of metabolism
• The methods which could be suggested under
retrospective genetic counseling are:
Contraception
Pregnancy termination.
Sterilization
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11. Areas of genetic counselling:
(A) Prenatal Genetic Counselling:
O Several different reasons a person or couple may seek
prenatal genetic counselling.
O The task is to assess risk to a couple of having a child
with genetic condition and to advise about options to
manage that risk, including reproductive options such as
artificial insemination and prenatal genetic diagnosis.
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12. (B) Pediatric Genetic Counselling:
O Families or pediatricians seek genetic counselling when a
child has features of an inherited condition.
O Any child who is born with more than one defect, mental
retardation or dysmorphic features has an increased
chance of having a genetic syndrome.
O Task is to establish a diagnosis in a child, provide
longitudinal care for the child, and advise the parents
about recurrence risk and options to deal with that risk.
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13. Steps of genetic counselling
History &
Physical
examination
• Include present, past history, detailed family history, obstetric history
including still births and abortions if any and exposure to teratogen.
• Careful examination of affected( photographs, measurement) and of
apparently unaffected individuals in the family.
Pedigree
• Construct a 3 generation pedigree diagram with their age, sex and
state of health.
Risk
assessment
• One of the most important aspect, often called “recurrence risk”. Requires
to take into account- Mode of inheritance
Analysis of pedigree or family tree
Results of various tests
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14. Diagnosis
• Most crucial step, confirm the diagnosis by available
diagnostic tests.
Communication
• Transmitting the information, with ample time for
discussion and questions.
Management
• Discuss available options for treatment of disease and
prevention of known complications or prevention of
genetic disorder( medical termination of pregnancy).
Support groups
• Group of patient or parents of children with same
disorder (patient support group)
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15. Prenatal diagnosis
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16. O Introduction: procedures which are used to detect
genetic disorders during early stages of pregnancy.
O Indications ;
1. To identify fetal disease when abortion is being
considered.
2. Advanced maternal age
3. Previous offspring with chromosomal anomalies
4. Positive maternal screening test
5. Mother having disease or being exposed to drug,
medication, or infections known to be associated with
congenital malformation.
6. Molecular DNA diagnosis (cystic fibrosis, fragile X).
7. Direct fetal treatment
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17. Methods of prenatal diagnosis
(a) Imaging- Ultrasound
MRI
(b) Fluid analysis- Amniocentesis
Cordocentesis
(c) Fetal tissue analysis- Chorionic villus sampling
(d) Maternal serum tests- α-feto protein
Triple test
Quad test
(e) Maternal cervix- Fetal fibronectin
Fluid
Bacterial culture 1711/03/2016

18. Non invasive
methods
Imaging-
USG, MRI
Maternal serum
analysis
Maternal cervical fluid
analysis
Invasive methods
Fluid analysis-
Amniocentesis,
Cordocentesis,
Fetal tissue analysis-
Chorionic villus
sampling
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19. Imaging
Ultrasound
O Real time USG
• In the 1st trimester most reliable
method to know gestational age.
• Fetal growth abnormalities-
by biometric measurement of biparietal diameter, femoral
length, or head or abdominal circumference.
• Fetal anomalies eg. Hydrocephalus, NTDs, duodenal atresia,
diaphragmatic hernia, renal agenesis, limb anomalies,
omphalocele, gastroschisis, hydrops.
• Also help in performing BPP, cordocentesis and other invasive
procedures
O Doppler USG- for velocimetry and detection of increased
vascular resistence due to fetal hypoxia.
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20. Fluid Analysis
Chorionic Villous Sampling
O Transvcervical or transabdominal
chorionic villous biopsy, which
provides fetal cells.
The placenta contains tissue
that is genetically identical to fetus.
O Timing: In first trimester,
shouldn’t be performed before 10wk,
commonly performed between 11 and 13 wks.
O Indications: for karyotype, enzyme assay, molecular
DNA genetic analysis.
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21. O Method of CVS: two ways to perform a CVS,
transabdominally (TA) and transcervically (TC),
depends on the location of the villi in the uterus.
Transabdominal approach-
When the villi are anterior,
under all aseptic precautions
ultrasound guided needle is
passed through abdominal
wall and the uterus to reach
the villi. A syringe attached
to the needle is used to
suction out a small amount
of villi.
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22. Transcervical (TC) approach-
When the villi are in the lower part of the uterus and
posterior, TC approach is used.
A thin flexible plastic catheter is carefully guided
through the cervix under ultrasound guidance to the
villi. A syringe attached to the catheter is used to
suction out a small amount of villi as the catheter is
withdrawn.
O The CVS procedure collects larger samples and
provides faster results than amniocentesis.
O Different from amniocentesis in that it does not allow
for testing for neural tube defects.
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23. O Associated risk/ Complications:
1.miscarriage/ fetal loss (1% - 2%).
2. Oromandibular limb hypoplasia.
3.Isolated limb reduction defect-
• Increased risk is associated with decreased gestational
age at the time of CVS, highest susceptibility when CVS
if performed before 9 wks.
• Mechanism: thromboembolization or fetal hypoperfusion
through hypovolemia or vasoconstriction (based on
assumption that caused by some form of vascular
disruption). The limbs and mandible are susceptible to
such disruption before 10 weeks’ gestation.
• Overall risk for transverse limb deficiency from CVS is
0.03%–0.10%
4.Rh- isoimmunization. 2311/03/2016

24. Amnicentesis
O USG guided percutaneous
withdrawal of amniotic
fluid for diagnostic purpose.
O Timing- between 14- 16wks.
O Indications:
• Karyotype (advanced maternal age)
• Fetal maturity
(L:S ratio, phosphatidylcholine or phosphatidylglycerol)
• Biochemical enzyme/amino acid/hormone analysis.
• Molecular genetic DNA diagnosis.
• α- fetoprotein(for NTDs) and
17-ketosteroid (for adrenogenital syndrome)
determination
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25. O Method of amniocentesis:
Performed transabdominally (TA). During the
procedure, a needle is passed through the abdomen
and into the amniotic sac under continuous ultrasound
guidance. The needle stilette is removed once the
needle is in the correct position. A small sample of
amniotic fluid (10–20ml) is then removed using a
syringe attached to the needle.
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26. Complications of amniocentesis:
1.Miscarriage (risk about 1%).
Before 14 weeks of gestation (early amniocentesis)
has a higher fetal loss rate.
2.Preterm labor (stimulation of uterine contraction) or
PROM.
3.Injury to fetus
4.Placental puncture and bleeding with secondary
damage to fetus.
5.Infection
6. Maternal sensitization to fetal blood (Rh-
isoimmunization) :- Anti D immunoglobulin to be
given to Rh –ve mother.
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27. CVS Amniocentesis
What does it involve? Small sample of
placenta under
ultrasound guidance
small sample of
amniotic fluid under
ultrasound guidance
When is the
procedure usually
performed?
Between 10 and 14
weeks of pregnancy
After 15 weeks of
pregnancy
What is the risk of
miscarriage?
About 1 to 2 in 100
women (1-2%)
About 1 in a 100
women (1%)
What technique is
used?
transabdominally (TA)
and transcervically
(TC)
transabdominally (TA)
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28. Cordocentesis
O Cordocentesis, or PUBS
(Percutaneous Umbilical Blood
Sampling), is the sampling of
blood from the umbilical cord.
O Objective: (a) prenatal diagnosis and (b) fetal
therapy.
O Timing: can be performed as early as 16 wks of
gestation but commonly performed between 18-22
wks of gestation for prenatal diagnosis.
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29. O Indication of cordocentesis:
(a) Prenatal diagnosis:
• Detection of anemia, hemoglobinopathies,
thrombocytopenia, acidosis, hypoxia, polycythemia
• Immunoglobuline M antibody response to infection
• Rapid karyotype and molecular DNA genetic
diagnosis.
(b) Fetal therapy:
• Transfusion or administration of drugs. 2911/03/2016

30. O Method of cordocentesis:
Under ultrasound guidance needle is inserted in the
umbilical vein within the umbilical cord at its placental
end or fetal end. Upon entering the umbilical cord, the
stylet is removed and fetal blood is withdrawn into a
syringe attached to the hub of the needle.
The needle is withdrawn, then the puncture site is
monitored for bleeding, and the fetal heart rate is
assessed. After this procedure, the fetal heart rate and
uterine contraction are monitored for 1-2 hours.
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31. O Complications of cordocentesis:
• Pregnancy loss, overall fetal loss risk of 1- 2%.
• Transient fetal bradycardia, manifestations of a
vasovagal response caused by local vasospasm, more
with umbilical artery puncture.
• Bleeding from the puncture site, cord hematoma.
• Fetomaternal hemorrhage
• Premature labor
• Infection
• Rh iso- immunization
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32. Maternal serum test
(A) α- feto protein:
Incresed Decreased
• Twins Trisomies
• NTDs Aneuploidy
• Intestinal atresia
• Fetal demise
(B) Triple test: can detect 70% of Down syndrome
• Unconjugated estriol ↓ed
• α- feto protein ↓ed
• β-HCG ↑ed
(C) Quad test: can detect 80% of Down syndrome.
• Unconjugated estriol ↓ed
• α- feto protein ↓ed
• β-HCG ↑ed
• Inhibin ↑ed
[Note: if only 1st trimester quad screen is used, α-feto protein is
recommended as a 2nd trimester follow up] 3211/03/2016

33. Down syndrome screening:
(A) 1st trimester:
• Fetal nuchal translucency (NT) thickness alone
≤70%
• NT with β-HCG & PAPP-A 87%
(PAPP-A = Pregnancy Associated Plasma Protein- A)
(B) 2nd trimester:
• Triple test 70%
• Quad test 80%
(C) Integrated screen:
1st trimester screen + 2nd trimester screen detect 95%3311/03/2016

34. Maternal cervix
O Fetal fibronectin: indicates risk of preterm birth.
O Bacterial culture: identifies risk of fetal infection
(group B streptococcus, Neisseria gonorrhoeae).
O Fluid: determination of PROM.
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35. Fetal Therapy
O Intervention for the purpose of correcting or treating a
fetal anomaly or condition.
O Types:
(A) Non invasive (Pharmacological) fetal therapy
(i) Preventive
(ii) Therapeutic
(B) Invasive (Surgical) fetal therapy
(i) Cordocentesis/ intra uterine transfusion
(ii) Fetal surgery
(iii) Treatment of Twin To Twin Transfusion
(iv) Stem cell therapy
(v) Gene therapy
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36. O Preventive pharmacotherapy example
Neural tube defect- 0.4mg/day folic acid for at least
one month to all women planning for pregnancy and
4 mg folic acid to women with prior child NTD at
least one month preconception and 12 weeks after
conception.
O Therapeutic pharmacotherapy examples
(A) Congenital Adrenal Hyperplasia- treatment
should begin as early as 4th to 6th week of pregnancy.
Oral dexamethasone to mother with dose 0.5 to 2
mg/kg/day.
Then treatment is continued to term in female
positive for genes and stopped in males after
confirmation of diagnosis by CVS or Amniocentesis.
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37. (B) Fetus with maternal SLE
Risk of complete heart block because of damage to
AV node.
Prevention: oral Dexamethasone 4mg/day to mother
during pregnancy.
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O Surgical (invasive) fetal therapy
In utero surgery may be beneficial in :
• Bladder outlet obstruction (PUV)
• Diaphragmatic hernia
• Cystic Adenomatoid Malformation
• Sacrococcygeal Teratoma
• Tracheal Atresia/ stenosis
• Neural Tube Defect
Twin – Twin Transfusion Syndrome (TTTS)
• In monochorionic twins, imbalance of blood flow due to
vascular communications in placenta.
• Therapy for TTTS- Serial reduction amniocentesis
Photocoagulation (LASER) of
anastomosis

39. O Stem Cell Therapy
Hematopoetic stem cell can give rise to complete
blood system, potential for treatment or even cure of
many hematopoetic diseases.
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