PRENATAL DİAGNOSİS AND
APPROACH TO A SYNDROME
Arthur Bodurie Calvin Garber(DMLS, BMLS and MScMM)
Molecular Biology (Human Genetics)
Faculty of Medical Laboratory Sciences and Diagnostics
Molecular Biology Department
Objectives
At the end of the lecture
1. Student should be able to differentiate between prenatal screening and
diagnosis
2. The importance of prenatal screening and diagnosis
3. Samples types been used in carrying out prenatal screening and diagnosis
4. Processes involve in carrying out Prenatal screening and diagnosis
PRENATAL DİAGNOSİS
The detection of a genetic or a structural abnormality
before birth
Not to be confused with prenatal screening
Ultimate goal is to inform couples about the risk of a
birth defect or genetic disorder in their pregnancy and
give them the chance to make informed choices on
how to manage the risk
History of prenatal diagnosis
Has it beginings in 1966, when Steele and Breg
showed that the chromosome make up of a fetus can
be determined by culturing cells from the amniotic
fluid
At that point the link between late maternal age and
Down syndrome risk was known
TYPES OF PRENATAL DIAGNOSTIC
PROCEDURES
Chorionic villus sampling (CVS)
Amniocentesis
Non-invasive
The accepted criterion for prenatal diagnosis is to
have a safe procedure
Which is not going to cause harm to the fetus or
miscarriage and other complications
WHAT ARE WE LOOKİNG FOR
A full and accurate family history is a corner stone in the
genetic assessment and counseling process.
The 1st and most important step in the diagnosis of
genetic disorders is construction of a family tree
The pattern of inheritance can be shown from the pedigree
vertical transmission in autosomal dominant disorders,
horizontal transmission in autosomal recessive disorders
and
oblique transmission in X-linked recessive disorders
REASONS FOR CARRYING OUT
PRENATAL DIAGNOSIS
Advanced maternal age.
Previous child with de novo chromosomal
aneuploidy.
Presence of structural chromosome abnormality in
one of the parents.
Family history of a genetic disorder that may be
diagnosed or ruled out by biochemical or DNA
analysis.
Family history of an X-linked disorder for which
there is no specific prenatal diagnostic test
Risk of a neural tube defect
Maternal serum screening and ultrasound screening
ADVANCED MATERNAL AGE
What is considered advanced maternal age might change from
centre to centre but it is usually beyond 35 or 37 would be
considered advanced maternal age
Main risk factor for advanced maternal age is the risk for Down
syndrome
Women in which age groups are more likely to give birth to
a baby with Down syndrome?
PREVİOUS CHİLD WİTH DE NOVO
CHROMOSOMAL ABNORMALİTY
Parents of a child with a chromosomal abnormality could
be normal...but we still need to check
There still might be an increased risk for chromosomal
abnormality in a subsequent child
Could be parental mosaicism
But in majority of the cases the explanation is unclear
PRESENCE OF STRUCTURAL
ABNORMALİTY İN ONE OF THE
PARENTS
Based on the type of abnormality, the risk of a
chromosomal abnormality in a child changes
FAMİLY HİSTORY OF A GENETİC DİSORDER
THAT MAY BE DİAGNOSED OR RULED OUT
BY BİOCHEMİCAL OR DNA ANALYSİS
Most diseases in this group have a 25% or 50% risk of recurrence.
These are cases:
Where the parents have been diagnosed as carriers in a population
screen
Where a previous child had been born with a condition
Where one of the parents have an autosomal dominant condition
Even before DNA analysis was possible, some biochemical disorders
could be diagnosed
Mitochondrial disorders pose special challenge for prenatal diagnosis
FAMİLY HİSORY OF AN X-LİNKED CONDİTİON
When there is nothing else to do we can do fetal gender
determination
Pre-implantation genetic diagnosis is also made possible
Perhaps do a gender determination first and then do a full
molecular genetic analysis
RİSK OF A NEURAL TUBE DEFECT
First and second degree relatives of patients with neural
tube defects are eligible for prenatal diagnosis due to an
increas risk for neural tube defects.
Do we need an invasive test for this?
MATERNAL SERUM SCREENİNG
AND ULTRASOUND EXAMİNATİON
When fetal abnormalities are suspected on the basis of
routine screening by maternal serum screening and fetal
ultrasound examination, genetic assessment and further
testing is recommended
MATERNAL SERUM SCREENİNG AND
ULTRASOUND EXAMİNATİON
When fetal abnormalities are suspected on the basis of
routine screening by maternal serum screening and
fetal ultrasound examination, genetic assessment and
further testing is recommended
METHODS USED FOR PRENATAL
DİAGNOSİS AND SCREENİNG
INVASIVE TESTING METHODS
1. Amniocentesis
It referres to the process of inserting a needle into the
amniotic sac and removing a sample of amniotic fluid
(approx. 15-20 ml) transabdominally using a syringe
Amniotic fluid contains cells of fetal origin that can be
cultured for diagnostic tests
Performed as an outpatient around 15-16 weeks after
the first day of the last menstrual period
If performed earlier there might be complications.
We can also look at alpha-fetoprotein (AFP) to detect
open NTDs
AFP and Ultrasonographic scanning at 18 and 19 weeks
gestation can detect 99% of fetuses with spina bifida and
almost all fetuses with anenchephaly
Diagnose > 100 disorders, cells analyzed for chromosomal and
biochemical disorders
Risk of infection and spontaneous abortion
Normally only used when:
Advanced maternal age
History of chromosomal disorder
Parent with chromosomal abnormality
Mother carrier of X-linked disorder
Known genetic disorder (single gene disorder)
Complications of amniocentesis
1 in 1600 risk of inducing miscarriage over the baseline of 1-2% for any pregnancy
at the 15-16 weeks of gestation
When done earlier the spontaneous abortion risk is 3 fold higher
The only congenital anomaly found to be increased in early amniocentesis is
talipes equinovarus (Club-feet) from 0.1-0.3% to 1.3%
Other complications are rare but present:
Leakage of amniotic fluid
Infection
Injury to the fetus
2. Chorionic villus sampling (CVS)
Involves the biopsy of tissue from the villus of the chorion
transcervically or transabdominally
Generally performed around 10-12 weeks
The villi are derived from extraembryonic part of the blastocyst
USG is used to determine the best appraoch to taking the sample
There is an additional increase in risk of fetal loss approximately 1%
over the already present 2-5%
NON INVASIVE TESTING METHODS
Ultrasound screening
Maternal serum AFP
First and second trimester maternal serum screening
Isolation of fetal cells from maternal circulation
Screening for Down Syndrome and other
aneuploidies
The leading indication for an invasive prenatal testing procedure
is the increased risk for chromosomal aneuploidies because of
maternal age
More than 70% of babies with Down syndrome are born to
women under the age of 35
A group of maternal serum markers have been carefully chosen
to be used in screening
APPROACH TO A SYNDROME
What is a Syndrome?
Pattern of anomalies (or dysfunctions) in different organ
systems with a common ethiology
The abnormalities
Malformations: A developmental defect leading to a total
or partial destruction or change in the normal configuration
of an organ
Intrinsically abnormal developmental process
The organ never had a chance to develop normally from
conception
Minor or major (impair vaibility and needs intervention)
Deformation: Distortion by a physical force of an
otherwise normal structure e.g. uterine
malformation
Disruption: Destruction of a tissue that was
previously normal
Dysplasia: Abnormal cellular organization within
tissue resulting in structural changes
CONGENITAL DEFECTS
ETIOLOGICAL (CAUSAL)
CLASSIFICATION
