Genetic testing: Past, present, future

What is Genetic Testing?

A genetic test is the analysis of human

DNA, RNA, chromosomes, proteins, or
metabolites in order to detect alterations
related to a heritable disorder

The ultimate goal is to recognize the

potential for a genetic condition at an
early stage
• Identifies chances in genetic
material(chromosome,genes,DNA,protein)
– The benefits of test
– Limitation of test
– Possible consequence of test
– Called informed consent
• Before genetic testing(by genetic counselor and
nurse)
• Genetic test performed from the sample of blood,
hair, skin, amniotic fluid, chorionic villus sample, or
tissues(look for chromosome, protein, DNA
depending n specific disease).
• [Link] lab report the treatment is given.
• Options Available for Fetal Diagnosis
– Screening
– Diagnostic
– Pictures, Examples
• Options for Pregnancy Management
– Termination
– Continuation
– Adoption
 What is a Birth Defect?
• “Congenital anomaly”
• Any abnormality of structure and/or function
present at birth
• > 4,000 different known birth defects ranging
from minor to serious
• Serious abnormalities lead to mental or physical
disabilities or even death
• Birth defects are the leading cause of infant
mortality & significant cause of premature death,
chronic illness and long-term disability
 What is the Risk of Having a
Fetus with an Abnormality?
• Overall risk – ~ 4%
• Worldwide - 6 million affected babies born/year
• U.S. - 150,000 affected babies born/year
• Most common abnormalities
– Congenital Heart Disease -- 8/1000
– Trisomy 21 – 1/700
– Neural Tube Defect -- 1/1000
– Cystic fibrosis – 1/3000
Types of Genetic Disorders
Chromosomal
Ex. Down Syndrome, Turner Syndrome
Single Gene
Ex. Sickle Cell Anemia, Cystic Fibrosis
Complex
Ex. Birth defects, most cancers
 Genetic Screening
Purpose - to detect
Chromosomal Abnormalities
DNA changes
Protein/biochemical changes
 Prior to Conception?
• Identify women/couples at risk
– Family history: birth defects or genetic dz
– Medications: Coumadin, Accutane
– Exposures: smoking, EtOH, drugs
• Refer to genetic counselor
• Consider carrier testing
– Cystic Fibrosis, Sickle Cell, Tay-Sachs
• Folate -  risk of NTD
 During pregnancy?

• Screening vs. diagnostic testing

• Provide information early
• Personal decision
• Factors that may be considered
– Desire to terminate if an abnormality is found
– Desire to have as much information for
preparation
– Delivery planning
 What is a Screening Test?
• A test done to identify a disease or defect
by the application of tests, examinations or
other procedures
• Provides individual RISK ASSESSMENT
• Ads:  number of procedures done for
diagnosis & therefore,  procedure-related
complications
• Disads: not diagnostic, may miss target
 What is a Diagnostic Test?
• A test that will definitively identify a
disease or defect
• Prenatal diagnostic test
– Chromosomal abnormality (aneuploidy),
gene change (Sickle cell)
• Ads: DEFINITIVE ANSWER
• Disads: Risks associated with the
diagnostic procedure
 Some examples of genetic
tests
• Prenatal screening
• Newborn screening
• Carrier screening
 Prenatal Screening
• This can detect a disorder before a baby is born.
• An ultrasound test is used to determine if the fetus is
at a high or low risk from a genetic disorder.
• Disorders are diagnosed by examining a small
amount of fetal cells. This carries a small risk to the
fetus.
• If diagnosed early in the pregnancy, there is still the
possibility of abortion.
• Prenatal screening is sometimes seen as
controversial.
• Family history
• Ultrasound (US)
– Introduced in the 1950s
• Amniocentesis
– First done in 1877 (for polyhydramnios)
– First done for chromosomal studies in 1966
– Common since the 1970s
• Chorionic villus sampling (CVS)
– First done in 1968
– Greater acceptance in 1980s-90s
• Rapid expansion of serum & US screening options,
wide-spread use – 1990s to present
 1st Trimester US
What Can We See?
• Markers of Aneuploidy & Congenital Heart Disease
  Nuchal translucency
– Absent nasal bone
– Tricuspid regurgitation
 1st Trimester US
What Can We See?
Normal Fetus Anencephaly
 2nd Trimester Ultrasound
What Can We See?
• Lethal anomalies
– Anencephaly
– Skeletal dysplasias
• Moderate to severe anomalies
– Congenital diaphragmatic hernia
– Heart defects
– Neural tube defects
• Relatively minor abnormalities
– Cleft lip/palate
– Club foot
– Polydactyly
 Anencephaly

[Link]
[Link]
Neural Tube Defects
Gastrochisis
Bilateral Cleft Lip & Palate
Club Foot & Polydactyly
Chorionic Villus
Sampling
• 10-13 weeks
• Trophoblasts cultured
• Advantages
– Early diagnosis
• Disadvantages
– Loss rate 0.5-1%
– 1% risk of confined
placental mosaicism

[Link]
 Amniocentesis
• > 15 weeks
• Remove 15-20 ml of amniotic fluid
• Amniocytes cultured
• Advantages
– Can test AFP levels.
• Disadvantages
– Loss rate 0.1-0.5%
– Later diagnosis
 Fetal Blood Sampling
(Cordocentesis)
• Removal of blood from umbilical cord
• Rarely done
• Done when diagnostic information
can not be obtained through
amniocentesis, CVS, US or the
results of these tests were
inconclusive
• Performed after 17 weeks
• Potential indications: suspected fetal
infection, anemia, thrombocytopenia
• Loss rate - 2%
 Types of Tests
Diagnostic Used to confirm a diagnosis based on physical signs

Predictive Used to detect gene mutations associated with disorders that

appear later in life

Carrier Used by people with a family history of recessive genetic

Identification disorders
Prenatal Used to test a foetus when there is risk of bearing a child with
metal or physical disabilities

Newborn Used as a preventative health measure once the baby is born

Screening

Forensic Used to identify an individual for legal purposes

testing

Research Used for finding unknown genes and identifying the function of a
testing gene
 Genetic testing includes:

1. Biochemical genetic testing - assay

for specific metabolites that indicate
a genetic disease
2. Cytogenetic testing - examination of
the chromosomes for visible
alterations that indicate a genetic
defect
3. Direct genetic testing - examination
of DNA to determine if mutations are
present
 Before DNA testing, diagnostic genetic testing
relied on the detection of phenotypes and/or
metabolites as well as the visualization of
chromosomes.

In some cases, these tests are still used

Taste test - baby with salty-tasting skin –
today
cystic fibrosis
Color of urine - black urine disease –
alkaptonuria
Green ring around iris - copper build up –
Wilson’s disease
Blood test for high levels of phenylalanine –
PKU
Chromosomal abnormalities –
Down Syndrome (trisomy chr 21)
 Biochemical genetic testing
determine if enzymes in the body are abnormal in some w

•performed on a blood, urine, spinal fluid, or other

tissue sample

•the disease is usually the result of a mutation that

causes an enzyme to be absent, unstable, or to have
altered activity

•diseases often called "inborn errors of metabolism"

because they are present at birth and affect how the
body's metabolism works
 Examples of disorders that can be
detected using enzyme-activity assays
•Galactosemia – galactose metabolism - galactose-
1-phosphate uridylyltransferase (type 1
galactosemia)

•PKU – phenylalanine metabolism - phenylalanine

hydroxylase

•Lesch-Nyhan - purine metabolism - hypoxanthine

guanine phosphoribosyltransferase (HPRT)

•Maple syrup urine disease – amino acid

metabolism - proteins of the branched-chain alpha-
keto acid dehydrogenase complex
 Cytogenetic Testing
Used to detect visible chromosomal abnormalities including

Visible alterations in the structure of

chromosomes can include:
•Large Deletions
•Inversions
•Translocations

Alterations in the number of chromosomes

•Down syndrome
Cytogenetic testing - Down syndrome

normal abnormal

Images from: [Link]

Cytogenetic testing - Deletions
Cytogenetic testing - Deletions
 Direct genetic testing
examination of DNA (or RNA) for
the presence of mutations

Direct genetic testing analyzes the sequence of a

person’s DNA to determine if a mutation is
present.
 What is a SNP (pronounced SNIP)?
A SNP is a Single-Nucleotide Polymorphism

- a mutation or change in a DNA molecule that is

usually caused by a mistake made during
replication of our chromosomal DNA

5’-ACGTACCGGT-3’

5’-ACGTACTGGT-3’
 Diagnostic Testing
used to confirm or rule out a known or suspected
genetic disorder in a person with disease symptoms

Issues to consider:
•Diagnostic testing is used to confirm diagnosis of
genetic defect
•Confirming a diagnosis may alter medical
management for the individual (PKU)
•Diagnostic testing of an individual may have
reproductive or psychosocial implications for other
family members
 Predictive Testing
offered to individuals who do not have symptoms at the
time of testing but have a family history of a genetic
disorder
Two types
Presymptomatic - development of disease is certain
when the mutation is present (HD)
Predispositional - development of disease is
possible when the mutation is present (breast
cancer)

Some issues to consider:

• medically indicated if early diagnosis beneficial
• can influence life-planning decisions
• can have psychological ramifications - may require patient
assessment & counseling
 Carrier Screening
• This involves testing prospective parents for diseases
that they show no symptoms of, but may carry a
recessive gene for.
• A blood sample or cheek cell sample is analysed to
determine whether either parent carries a faulty gene.
• If both parents carry a specific faulty gene, the chance
of the fetus receiving the gene from both parents is
25%, and the chance of being a carrier is 50%.
• If both parents carry a faulty gene, they may decide to
have prenatal testing on the fetus.

Some issues to consider:

• Identifying carriers allows reproductive choices
• Genetic counseling and education should accompany carrier testing
because of the potential for personal and social concerns
 Newborn Screening
identifies individuals who have an increased chance of having a
specific genetic disorder so that treatment can be started as soon
as possible

•performed on a small blood sample, which is taken by

pricking the baby’s heel

•a parent will usually only receive the result if it is positive.

•if the test result is positive, additional testing is needed to

determine whether the baby has a genetic disorder

Issues to consider:
•usually legally mandated, tests vary from state to state
•performed routinely at birth
Texas Newborn Screening Quick Reference to Newborn Screening Disorders
Biotinidase Deficiency - BIOT is an enzyme deficiency that occurs in about 1 in 60,000 U.S. newborns and
can result in seizures, hearing loss, and death in severe cases. Treatment is simple and involves daily doses of
biotin.
Congenital Adrenal Hyperplasia – 21-Hydroxylase Deficiency - CAH is caused by decreased or absent
production of certain adrenal hormones. The most prevalent type is detected by newborn screening in about 1 in
9,000 Texas newborns. Early detection can prevent death in boys and girls and sex misassignment in girls.
Treatment involves lifelong hormone replacement therapy.
Congenital Hypothyroidism Inadequate or absent production of thyroid hormone results in CH and is
present in about 1 in 2,000 Texas newborns. Thyroid hormone replacement therapy begun by 1 month of age can
prevent mental and growth retardation.
Galactosemia – Galactose-1-Phosphate Uridyltransferase (GALT) Deficiency - Failure to metabolize the milk
sugar galactose results in GAL and occurs in about 1 in 50,000 U.S. newborns. The classical form detected by
newborn screening can lead to cataracts, liver cirrhosis, mental retardation and/or death. Treatment is elimination
of galactose from the diet usually by substituting soy for milk products.
Homocystinuria - HCY is caused by an enzyme deficiency that blocks the metabolism of an amino acid that
can lead to mental retardation, osteoporosis and other problems if left undetected and untreated. The incidence is
approximately 1 in 350,000 U.S. newborns. Treatment may involve a restricted protein diet and supplemental
medicines, including Vitamin B6.
Maple Syrup Urine Disease (MSUD) - MSUD is a defect in the way that the body metabolizes certain amino
acids and is present in about 1 in 200,000 U.S. newborns. Early detection and treatment with a special restricted
protein diet can prevent death and severe mental retardation. There is an increased risk in Mennonites.
Medium Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency - The most common disorder in the
way the body metabolizes fatty acids is called MCAD deficiency. Undetected, it can cause sudden death. Treatment
is simple and includes ensuring frequent food intake. The incidence from newborn screening is not yet known, but
is thought to be approximately 1 in 15,000 U.S. newborns.
Phenylketonuria (PKU) - An enzyme defect that prevents metabolism of phenylalanine, an amino acid
essential to brain development, is known as PKU and occurs in approximately 1 in every 23,000 Texas newborns.
Undetected and untreated with a special restricted protein diet, PKU leads to irreversible mental retardation.
Texas Newborn Screening - Total number of disorders screened for is 27
Sickle Cell Disease (SCD) – includes Sickle Cell Anemia (Hb SS), Sickle Beta Thalassemia (Hb S/?Th)
and Sickle-Hemoglobin C Disease (Hb S/C) - Sickle cell anemia is the most prevalent SCD and causes clogged
blood vessels resulting in severe pain and other severe health problems. Newborn screening detects about 1 in
2,500 Texas newborns with SCD annually. Persons of African or Mediterranean descent are at an increased risk.
Early treatment with daily penicillin prevents death in the first few years of life. (3)
Tyrosinemia Type I -TYR is caused by a deficiency in the liver of one enzyme that breaks down tyrosine. If
not treated, the condition causes severe liver disease and other health problems. Treatment consists of
medication including vitamin D and nitisinone, and a special restricted protein diet. Estimated incidence is 1 case
in every 100,000 live births. (1)
Fatty Acid Oxidation (FAO) Disorders include Carnitine Uptake Defect (CUD), Long-Chain
Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHAD), Trifunctional Protein Deficiency (TFP) and Very-
Long-Chain Acyl-Co A Dehydrogenase Deficiency (VLCAD) - Disorders besides MCAD deficiency, other FAO
disorders may be detected through newborn screening. They are usually described in categories based on the
length of the fatty acid involved. Undetected and untreated they can cause seizures, coma, and even death.
Treatment may include a low fat diet, frequent food intake, supplementation with L-Carnitine (Carnitor) and
medium chain triglycerides.
Organic Acid (OA) Disorders include 3-Methylcrotonyl-CoA Carboxylase Deficiency (3MCC), Beta-
Ketothiolase Deficiency (BKD), Glutaric Acidemia Type I (GAI), Hydroxymethylglutaric Aciduria (HMG),
Isovaleric Acidemia (IVA) Methylmalonic Acidemia(MMA) (Cbl A and Cbl B forms) ( Cbl A,B),
Methylmalonic Acidemia (mutase deficiency form) (MUT), Multiple Carboxylase Deficiency (MCD) and
Propionic Acidemia (PROP) - Organic acidemias are a group of metabolic disorders that lead to accumulation of
organic acids in the blood and urine and may be detected in newborn screening through analysis of acylcarnitine
profiles. Symptoms can be diminished by restricting protein in the diet and supplementation with vitamins and/or
L-Carnitine.
Urea Cycle Disorders (UCD) include Argininosuccinic Acidemia (ASA) and Citrullinemia
(CIT) - A UCD is a genetic disorder caused by a deficiency of one of the enzymes responsible for removing
ammonia from the blood stream. Some UCDs may be detected as a part of newborn screening. They are
characterized by seizures, poor muscle tone, respiratory distress, and coma, and result in death if left undetected
and untreated. Treatment is by a special restricted protein diet and medications including phenylbutyrate to
remove ammonia.
 Benefits of Genetic
Screening
Diagnosis
Reduce testing
Appropriate intervention
(prevention, management,
treatment)
Informed decisions
Reproductive choices
 Genetic Counseling
Genetic counseling is a process, involving an individual or family,
with the goal of evaluating, confirming, diagnosing or excluding a
genetic condition.

A genetic counselor can help by providing information about the

pros and cons of the test and discussing the social and emotional
aspects of testing.

Genetic counseling may involve:

discussion of natural history and the role of heredity;

identification of medical management issues;

calculation and communication of genetic risks;

provision of or referral for mental and social support