Genetic Screening and Prenatal Diagnosis

Genetic Screening and
Prenatal Diagnosis
Prenatal diagnosis …
• gives parents an opportunity to prepare
psychologically for the birth of a child with a
genetic/developmental abnormality.
• provides, for an increasing number of
genetic diseases, an opportunity for
therapeutic intervention before delivery by
surgical correction, cell repair or
replacement technologies, …
• gives the parents the choice of terminating
the pregnancy if they choose to do so.
Some methods available …
• AMNIOCENTESIS
• CHORIONIC VILLUS SAMPLING
• ULTRASONOGRAPHY
• ALPHA-FETOPROTEIN
Amniocentesis
1 Fluid (~20 mL) is withdrawn from amniotic

heritabilitycavity at 14 – 16 weeks
gestation
2 Fluid analysis for abnormal amniotic fetal
protein (AFP) levels: various conditions.
3 Cells are cultivated for chromosomal,
biochemical, or molecular (DNA) analysis.
4.Risk of procedural miscarriage is less than
1% with skilled operators (spontaneous
rate is 2-3% at 15 weeks).
CHORIONIC VILLUS SAMPLING
• Either transabdominal- a catheter is
inserted through the cervix into the
placenta to obtain the tissue sample
• or transcervical route- a needle is
inserted through the abdomen and
uterus into the placenta to obtain
tissue sample.
• Available at 11- 12 weeks gestation.
• Miscarriage rate is 2-3% when
technical conditions are optimum.
Ultrasonography
• Offered at 18-19 weeks gestation.

• Detects gross malformations but misses
many significant problems.
• Essential as a monitoring tool for
amniocentesis and chorionic villus
sampling.
• Example - Hand of fetus with Holt-Oram
syndrome has only 4 digits (3 fingers and a
‘thumb’)
ALPHA-FETOPROTEIN
• Protein, produced by fetal liver, is excreted by
kidneys into amniotic fluid and crosses the placenta
into the maternal circulation.
• At 10-20 weeks gestation:
• Elevated AFP in maternal blood:
- NEURAL TUBE DEFECT (open lesion)
• Decreased AFP in maternal blood:
- TRISOMY 21 (Down’s syndrome)
- TRISOMY 18 (Edward’s syndrome)
Maternal AFP is a good screening tool for open

neural tube defects but weak for trisomy 21
Other approaches to prenatal diagnosis
• Fetoscopy - Direct observation of fetus at 18-20

weeks gestation with an endoscope. Possibility
of fetal skin biopsy or blood sampling. High risk
• Cordocentesis - Collection of fetal blood from
umbilical cord either during fetoscopy or with
ultrasonic guidance. High risk
• Maternal blood analysis - Analysis of unusual
components or unusual levels of normal
components in blood of the pregnant mother.
Fetal cells in maternal circulation.
1. Fetal cells are known to cross the placenta in small

numbers.
2. If techniques can be developed to isolate these fetal
cells, they can be subjected to analysis.
3. Monoclonal antibodies have been produced that are
specific for fetal cells.
However Fetal cells (lymphocytes) from previous
pregnancies may persist in the maternal circulation
for many years.
So the question is - Are you testing the cells of the
current conceptus or cells from a previous
conceptus?
Who are candidates for prenatal screening?
• Women of advanced maternal age.

• The risks of amniocentesis are balanced by the risk
of fetal abnormality at 35 years of age.
• Previous child with adenovo chromosome
abnormality. Example: The recurrence rate for
chromosome abnormality pregnancy for a 30 year
old woman with a trisomy-21 infant is 1 in 100 as
compared with 1 in 390 for other women of the same
age.
• Any Presence of structural chromosome abnormality
in one of the parents. Example: If either parent has a
21q21q Robertsonian translocation, the risk for a
trisomy-21 child is 100%.
• Family history of a single gene disorder that can be

diagnosed or ruled out by biochemical or DNA analysis.
Examples: Huntington disease, fragile Xsyndrome, cystic
fibrosis, hemophilia A and B,retinoblastoma,
phenylketonuria, etc., etc., etc.
• Family history of an X-linked disorder for which there is
no specific prenatal diagnostic test available. Parents
may opt to terminate all male fetuses when the mother is
a confirmed carrier for a severe and untreatable X-linked
disease.
• Family history of a neural tube defect. The couple would
be offered maternal blood AFP testing and a detailed
ultrasonic examination of the fetus.
• Family history of congenital anomalies. Examples:

Congenital heart disease, congenital diaphragmatic
hernia.
• Prior knowledge prepares the parents
psychologically and may provide an opportunity for
prompt surgical intervention.
• With the general acceptance of routine ultrasonic
prenatal examinations, many couples are being
referred to genetics clinics for further investigation.
• Most idiosyncrasies have little predictive value for
serious genetic disease and counseling is difficult.
Should screening be offered for all pregnancies or just to couples
at a predefined risk?
Criteria for a screening program.
• Disease - Has the disease a high incidence?

Is it serious? Can it be treated?
• Tests - Are accurate, reliable, inexpensive
and are non-invasive tests available?
• Acceptability and followup - Would testing be
acceptable and readily available to the target
population? Is effective post-test counselling
available?
Routine Prenatal Screening
• 16 weeks - Neural tube defects (NTD).

Maternal serum AFP (open lesion only)
and/or ultrasonic investigation (all NTDs)
• Down syndrome
• 18-20 weeks - Routine ultrasonic

investigation
Additional Neonatal Screening
• Most populations - Phenylketonuria,

hypothyroidism.
• Many populations – Galactosemia.
• Some populations - Sickle cell anemia,
Cystic fibrosis.
Screening of young adults before reproduction
to detect carriers
• Actual programmes
- Tay-Sachs disease in Ashkenazi Jews.
- Beta-Thalassemia in Mediterranean peoples.
• Possible programs
- Alpha Thalassemia in people of South East Asian
origin or ancestry.
- Sickle cell disease in people of Black African origin or
ancestry.
- Cystic fibrosis in people of Western European origin or
ancestry.

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Genetic Screening and

• CHORIONIC VILLUS SAMPLING

1 Fluid (~20 mL) is withdrawn from amniotic

• Offered at 18-19 weeks gestation.

Maternal AFP is a good screening tool for open

• Fetoscopy - Direct observation of fetus at 18-20

1. Fetal cells are known to cross the placenta in small

• Women of advanced maternal age.

• Family history of a single gene disorder that can be

• Family history of congenital anomalies. Examples:

• Disease - Has the disease a high incidence?

• 16 weeks - Neural tube defects (NTD).

• 18-20 weeks - Routine ultrasonic

• Most populations - Phenylketonuria,

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