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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
As of 10/19/08, there were ~1,633 genetic tests available
(www.genetests.org)
In the future, the number of genetic tests will increase as more
disease-causing genes are identified
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 today
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Taste test - baby with salty-tasting skin - 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
To determine if enzymes in the body are abnormal in some way
•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
Tay Sachs Disease – build up of GM2 gangliosides - DNA test is available but
does not detect all of the known alleles.
By performing a test for the enzyme that is deficient in Tay Sachs patients, betahexosaminidase A, more cases can be detected than through DNA testing.
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
Images from: http://members.aol.com/chrominfo/
abnormal
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’
Personal genome analysis
SNPs are used by genome analysis companies to make
predictions about your risk of developing certain diseases.
23and me https://www.23andme.com/
decodeMe http://www.decodeme.com/
assess your genetic risk for 31 diseases and traits based on current literature
Navigenics http://www.navigenics.com/
Specific types of genetic test?
1. Diagnostic testing
2. Predictive testing
3. Carrier testing
4. Newborn screening
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 Testing
Test to identify individuals who have a gene mutation for a disorder
inherited in an autosomal recessive or X-linked recessive manner
offered to individuals with family members who have a genetic condition, family
members of an identified carrier, and individuals in ethnic or racial groups known to
have an increased risk for a specific condition
If both parents are tested, the test can provide information about a couple’s risk
of having a child with a genetic condition
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.
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