FINAL LEC 3: Genetic Counseling, Testing, and Treatment Flashcards
Specialized healthcare service provided by professionals known as genetic counselors Primary aim: o To help individuals and families understand and make informed decisions about genetic conditions that may affect them or their offspring
GENETIC COUNSELING
- Health care professional with a master’s degree who can help patients & their families understand the inheritance pattern of a specific medical condition, evaluate the risk, & possibly navigate the path of genetic testing
- Other professionals who can provide counseling: physicians, nurse, social workers, & PhD geneticists
GENETIC COUNSELOR
____________ coined the term “genetic counseling” and what year
Sheldon C. Reed, 1947
First class of specially trained genetic counselors graduated from Sarah Lawrence College in Bronxville, New York
1971
33 programs in the United States offer a master’s degree in genetic counseling, and many other countries have programs
2018
University of the Philippines Manila offers Master of Science in Genetic Counseling (a 2-year degree program)
Philippines
Reasons to seek genetic counselling:
Family history of abnormal chromosomes
Elevated risk of single-gene disease Family history of multifactorial disease
Family history of cancer
Genetic counselling sessions:
Family history
Pedigree construction
Information provided on specific diseases, modes of inheritance, tests to identify at-risk family members Testing arranged, discussion of results and treatments
Links to support group, appropriate services, clinical trials follow-up contact
focuses on assessing and discussing the risk of genetic conditions or birth defects in a pregnancy
PARENTAL GENETIC COUNSELING
-Focuses on helping individuals understand their risk of developing certain genetic conditions that typically manifest in adulthood (cardiac, neurologic, & hematologic conditions)
-Predictive tests are introducing the “genetically unwell” or those “premanifest” state – people with mutant genes but no symptoms (yet)
GENETIC COUNSELING FOR ADULT-ONSET DISEASES
Medical tests that analyze an individual’s DNA to identify changes in specific genes/chromosomes
GENETIC TESTS
GENETIC TESTS PROVIDE VIEWS OF HUMAN GENOMES AT SEVERAL LEVELS:
- May detect single-base/copy number variants in individual genes
- May display/identify abnormal chromosomes/ chromosome numbers
- May assess variability across the genome
- May determine the entire protein-encoding part of the genome (exome) or the whole genome
“Gamete donor selection based on calculation” o Computer program that predicts the results of meiosis in the gametes of an individual
o Analyzes possible gamete phenotypes of the “recipient” (presumably a woman) & a “plurality of donors” (presumably men), considering penetrance and epistasis
o “Hypothetical offspring” o Also detects if potential parents are close blood relatives
Preconception and Prenatal
-Sperm are labeled with fluorescent markers: Xbearing sperm cells glow more intensely than Y-bearing sperm because the X chromosome is so much larger
o Sperm are collected and separate them into fractions that are enriched for X-bearing or Ybearing cells, to attempt to conceive a girl or a boy, respectively
Flow Cytometry
Enriches for X- or Y-bearing sperm, then intrauterine insemination or in vitro fertilization
Sperm selection
Sequences genes, exomes, and genomes and examines chromosomes of 1 cell of 8-celled embryo conceived in vitro; remaining embryo develops for a few days and is then implanted in the uterus
Preimplantation genetic diagnosis and sequencing
Tests DNA and chromosomes of chorionic villus cell
Chorionic sampling
Detects small deletion and duplications in archived cells from past unexplained pregnancy losses
Rescue karyotyping
Tests cell-free fatal (placental) DNA
Noninvasive prenatal diagnosis
Measure levels of biomarkers in pregnant woman’s blood
Maternal markers
Tests DNA and chromosomes of amniocytes
Amniocentesis
Goal: To identify genetic conditions or disorders early in life to enable timely medical intervention, treatment, or management
Newborns
Analytical chemistry technique that detects abnormal metabolites
Mass spectrometry
Aims
to detect certain genetic,
metabolic/congenital conditions shortly after birth, even before symptoms become apparent
DNA TESTING
Screen metabolites & DNA in heel stick blood sample for 50-plus actionable conditions
SCREENING
Sequence genomes of many newborns to assess clinical value
GENOME SEQUENCING
-Involves analyzing a child’s DNA to identify genetic variations, mutations, or abnormalities that may be associated with specific medical conditions or genetic disorders
-Range from single-gene tests that are done because symptoms match those of a known disease, to chromosome tests, to exome & genome sequencing
Children
Detects small deletions, duplications, & other CNVs associated with certain phenotypes
CHROMOSOMAL MICROARRAY ANALYSIS
Diagnoses unrecognized
syndromes/atypical cases; family comparisons distinguish de novo from inherited mutations in children
EXOME SEQUENCING
Reasons why adults take single-gene tests: 1. As part of diagnostic workups based on symptoms or other test results
2. To detect increased risk of developing a particular cancer
3. When considering having children, & wonder what traits and illnesses they might pass on
Adults
Preconception carrier tests for genetic diseases more prevalent among people of Jewish ancestry
Dor Yeshorim program
Tests athletes to identify carriers at risk for symptoms
Sickle cell disease
Preconception carrier tests for many single-gene diseases
Comprehensive carrier testing
Tests for heterozygotes for diseases more prevalent in certain population groups
Population carter screen
Y chromosome and mitochondrial DNA sequences identify paternal and maternal lineages, these and autosomal markers Identify distant cousins
Ancestry testing
Copy numbers of short tandem repeats (STR) in crime scene or disaster evidence
Forensics testing
Identify remains: risk for depression, PTSD: rapid infection diagnosis
Miltary
BRCA cancers, Alzheimer disease
Susceptibility
Drug efficacy, adverse effects, and dose
Pharmacogenetics
Identify genes contributing small degrees to a phenotype
Genome-wide association studles
Half of a child’s genome comes from the father
Paternity
Identify gene variants that extremely old people share
Centenartans
- Genetic testing after death Involve examining DNA samples obtained during an autopsy, tissue preservation, or using stored biological samples from the deceased person
- Disease diagnosis: Identify mutations in cells of deceased individuals
- History: identify remains - Human origins: compare genomes of modern & archaic humans
Posthumous
-A service that allows individuals to obtain information about their genetic makeup directly from a company w/o involving a healthcare professional/medical provider
- Marketed directly to customers via television, print advertisements, or the internet & the tests can be bought online or in stores
DIRECT-TO-CONSUMER (DTC) GENETIC TESTING
-Establish quality standards for all laboratory testing, including DTC genetic testing
-Aim to ensure accurate & reliable laboratory testing, regardless of where the testing is performed
-Control genetic testing of body materials for the prevention, diagnosis, or monitoring response to treatment of a disease or health impairment.
CLINICAL LABORATORY IMPROVEMENT AMENDMENTS (CLIA) IN THE U.S.
- Ordering the test 2. Sample collection 3. Sending the sample to the testing company 4. DNA analysis 5. Accessing the results through an online portal/mobile app
HOW DTC GENETIC TESTING WORKS
Certain individuals possess a genetic advantage that predisposes them to excel in specific sports of physical activities
Test for inborn athletic ability
Examines an individual’s genetic makeup to provide personalized dietary recommendations
Nutrigenetics testing
Focus on understanding how an individual’s genetic makeup influences their response to medications
Pharmacogenetic & pharmacogenomic testing
Procedure
o Customers mail in saliva/cheek brush scrapings that yield DNA
o They will receive list of variants of specific genes (with general physiological functions related to fitness & athletic ability) a few weeks later
INBORN ATHLETIC ABILITY
o Has an insertion/deletion polymorphism o “I” (insertion) allele: endurance athletes (triathlon athletes, mountaineers)
o “D” (deletion) allele: elite swimmers than other groups & is associated with increased power & strength with training
Angiotensin-1-converting enzyme gene (ACE)
1 genotype is more common among elite sprinters & another among endurance athletes
Alpha-actinin 3 (ACTN3)
- Nutrigenetics is the study of how genes determine the effects nutrients have on the body and health
- Offered by websites, along with general questionnaires about diet, exercise, & lifestyle habits
-Companies suggest dietary indications – a central issue in the prevention and etiopathogenesis of specific diseases – based on one’s personal genetic background
NUTRIGENETICS TESTING
People may react differently to the same dose of the same drug, even accounting for weight, gender, and age
PHARMACOGENETIC TEST & PHARMACOGENOMIC TEST
Detects a variant of a single gene that affects drug metabolism
Pharmacogenetic test
Detects variants of multiple genes/gene expression patterns that affect drug metabolism
Pharmacogenomic test
-An innovative medical approach that involves using genetic material to treat/prevent diseases
- Goal: to correct/modify defective genes within an individual’s cells to restore normal cellular function/provide therapeutic benefits
GENETIC TREATMENT
- Removing an affected body part 2. Replacing an affected body part/biochemical with a material from a donor
- Delivering pure, human proteins derived recombinant DNA technology
- Refolding correctly a misfolded protein 5. Blocking gene expression (gene silencing) 6. Using gene therapy to add wild type alleles w/o removing mutant alleles
- Using gene & genome editing to replace, delete or add alleles
- Drugs
TREATMENTS FOR SINGLE-GENE DISEASES:
Medicines are chemicals or compounds used to cure, halt, or prevent disease; ease symptoms; or help in the diagnosis of illness.
DRUGS
o Enzyme glucocerebrosidase is deficient or absent o Due to little/no enzyme: buildup of substrates -> lysosomes swell -> bursting cells
o Symptoms: enlarged spleen & liver, bone pain, & deficiencies of blood cells
o Variable in age of onset, severity of symptoms, & rate of progression
Type I Gaucher disease
Recombinant human enzyme infused to compensate for deficient or absent enzyme
Enzyme replacement therapy
Oral drug that reduces level of substrate so enzyme can function more effectively
Substrate reduction therapy
Oral drug that binds to patient’s misfolded protein, restoring protein
Pharmacological therapy
-AKA drug repositioning / drug profiling
-Process of identifying new therapeutic uses for existing drugs that were originally developed for different indications
-Less costly than developing new drugs
Examples:
o A failed cancer drug that helps children who have form of progeria (accelerated aging condition)
o Drug that treats erectile dysfunction by increasing blood flow to the penis improves leg muscle function in boys who have Becker muscular dystrophy
DRUG REPURPOSING
- Delivers working copies of genes to specific cell types or body parts, typically as parts of modified viruses that function as carriers (vectors)
- May require a single or a few treatments
1. Gene addition
2. Gene editing
3. Gene silencing
4. Stem cell therapy
GENE THERAPY
-Alters the DNA of a gamete or fertilized ovum, so that all cells of the individual have the change and the correction is heritable, passing to offspring
- Not being done in humans
GERMLINE GENE THERAPY
Corrects only the cells that an illness affects and is nonheritable, in which the recipient does not pass the genetic correction to offspring, unless the cells that give rise to gametes are inadvertently altered
SOMATIC GENE THERAPY
Can be genetically altered to secrete proteins into the circulation
ENDOTHELIUM
Immature muscle cells (myoblasts) given healthy dystrophin genes may treat muscular dystrophy
MUSCLE
To treat certain inborn errors of metabolism, only 5% of the liver’s 10 trillion cells need to be genetically altered
LIVER
Gene therapy can reach damaged lungs through an aerosol spray. Enough cells would have to be reached to treat hereditary emphysema (alpha-1-antitrypsin deficiency) or cystic fibrosis
LUNGS
Gene therapy can target skin cells to treat certain skin disorders, such as epidermolysis bullosa
SKIN
Cells are altered outside the body & then infused into the bloodstream through a vein
EX VIVO GENE THERAPY
“In the living body”, the gene & its vector are introduced directly into the body, such as through a catheter inserted & snaked to the appropriate organ
IN VIVO GENE THERAPY
Amplify specific DNA sequences from a DNA sample, generating large amounts of the target gene for further analysis, manipulation, or delivery into target cells
PCR
Manipulation & combination of DNA from different sources to create new DNA sequences that encode therapeutic genes or their modified versions
RECOMBINANT DNA TECHNOLOGIES
Restriction enzymes, CRISPR-Cas9
OTHER TECHNIQUES THAT CUT DNA
- Usually delivers the healing DNA with other DNA (mobile) - Uses the following as carriers: 1. Viral vectors a. Adeno-associated viruses (AAV) b. Lentiviruses c. Adenoviruses d. Retroviruses
2. Liposomes 3. Polymer-based vectors 4. Naked DNA
GENE TRANSFER
INITIAL SUCCESS (1980s)
o Had severe combined immune deficiency due to adenosise deaminase (ADA) deficiency
o Began enzyme replacement therapy, but within 2 years it stopped working
o Undergone gene therapy that would give her WBCs functional ADA genes
Ashanti (“Ashi”) Desilva
SETBACK (1999)
o Had ornithine transcarbamylase (OTC) deficiency & could not make a liver enzyme required to break down dietary proteins
o Trillion adenoviruses carried functional human OTC genes through a tube into his liver
o Viruses entered not only the hepatocytes as intended, but also macrophages that alert immune system
Jesse Gelsinger
- Not only delivers a gene to a specific part of the genome, but can replace a gene, remove a gene, or add a gene, & do so in multiple places or insert, correct, or delete multiple genes
Can be combined with genome sequencing to engineer an animal model of a family’s inherited disease, to refine diagnosis & reveal how the symptoms arise (family with thoracic aortic aneurysm & dissection)
CRISPR-Cas9 IN DIAGNOSIS & TREATMENT
o Reactivating the quiescent globin genes can treat the disease
o Use of induced pluripotent stem cells (iPS cells)-> CRISPR-Cas9 replaces 1 sicle cell mutation with a wild type of the copy of the beta globin gene
o Use CRISP-Cas9 to silence a gene that normally switches fetal hemoglobin production off after birth
Sickle cell disease
