Genetic Lecture exam 3 Flashcards
Why preform genetic testing
-Establish or confirm a genetic diagnosis
-Reproductive decision making: seeing what conditions your kids are predisposed to
-Prediction of future disease
-Aid in med mgmt: seeing what drugs are effective
Paradigm shift
-Going from gathering history, diagnosis hypothesis and confirming it with a test
-To ordering a test to forming a hypothesis and diagnosis based on it while doing a detailed history to confirm it
Genome
A person’s genetic blueprint
Genotype
Inherited from the parents, your “code”
Phenotype
Expression of the genotype based on environmental factors
-Can indicate something is wrong with the genotype
Aneuploidy
Chromosomal abnormality, a cell that does not contain a multitude of 23 chromosomes
-Essentially one of the chromosome pairs has an extra or one less
-Trisomy or monosomy
-Occurs due to a non-disjunction typically
Trisomy
Contains three copies in one chromosome
-Its better to have 3 than 1
Disjunction
-Normal
-Separation of chromosomes during cell division, into the typical pairs
Nondisjunction
-Abnormal
-Improper separation of chromosomes into their pairs, leading to trisomy and monosomy
-Usually the cause of the aneuploidy
-Occurs during meiosis 1/2
Cell free DNA
Genetic testing, prenatally that is minimally invasive
-Done through a maternal blood sample, as it contains floating fetal DNA
-The fetal cells when they perform apoptosis leaves DNA floating in the bloodstream, which enters the maternal bloodstream
-Significantly less invasive than amniocentesis or taking a fetal blood sample
Non invasive prenatal test (NIPT)
-Cell free DNA test
-Test for Trisomy 13, 18, 21 as well as sex chromosome differences
Down Syndrome
-Trisomy 21
-Risk increases with maternal age (1/800 births)
Characteristics
-Mentally challenged
-Low nasal bridge
-Epicanthal folds
-Protruding tongue
-Poor muscle tone
Turner syndrome
-Sex chromosome aneuploidy: can be tested prenatal
Female with only one X chromosome
Characteristics
-Absence of ovaries (sterile)
-Short stature
-Webbing of the neck (Neck looks super thick)
-Edema
-Underdeveloped breast, wide nipples
Klinefelter syndrome
-Sex chromosome aneuploidy: can be tested prenatal
Individual with 2X 1Y
Characteristics
-Male appearance
-Has female like breast
-Small testes
-Sparse body hair
-Long limbs
Indications for prenatal or ped testing
-Developmental delays
-Intellectual disabilities
-Dysmorphic features
-Family history
-FTT
-Atypical growth
-Cafe au lait spots
-Congenital defects
-Hearing loss
Seizures
-Atypical sexual development
Genetics
-Observing one gene at a time and finding an effect
-Where we are
Genomics
-Observing the entire genome and the interactions between genes and how they affect development
-Where we wanna go
Adenine (A) bond with
Thymine (T)
Guanine (G) bonds with
Cytosine (C)
Protein
50+ amino acids
Peptide
2 or more amino acids
Amino acids
3 bases- one codon
Cystic fibrosis
-Occurs in white people mainly
-Autosomal recessive, 1/29 white people are carriers
-CFTR gene
CFTR modulators
-Modulate the gene responsible for CF, targeting the root cause
-Corrects the malfunctioning protein
-Works well, adding decades to life but super super expensive
Best initial genetic tool
Family history
Family history
-Simplest, most inexpensive, underutilized genetic tool
NCCN genetic family high risk assessment: Breast cancer
-Testing for breast cancer susceptibility genes
-BRCA1, BRCA2 CDH1 PALB2 PTEN TP53
-Indicated for pt with breast cancer if they are under 50
-Or any age if they have multiple primaries, male breast cancer or Ashkenazi Jewish heritage
NCCN testing: Ovarian cancer
-Testing of pt with epithelial ovarian cancer is indicated at any age
-Family history, first or second degree relative with ovarian cancer
-All people with pancreatic cancer
-First degree relatives diagnosed with pancreatic cancer
BRCA 1/2
Raise the risk of cancer, both breast and ovarian
-Come from different chromosomes (1 is 17) (2 is 13)
-50-85% chance of developing breast cancer
-20-40% of developing ovarian cancer
decision making Post BRCA 1/2
May lead to preventative surgery like a mastectomy
-PARP inhibitors can be given for BRCA carriers
Sanger sequencing
-Sucks, historic gold standard
-2 per base pair
Next gen sequencing
-Massively parallel sequencing
-100-10000 of reads per base pair
Syndrome specific testing
-Only looking for specific genes, high positivity rate low unspecificity rate
Comprehensive testing
-Looking for everything, takes a while , low positivity rate, high unspecificity rate
Abnormal variation (mutation)
“harmful”
-Growing another set of ears
Normal variation (Polymorphism)
SNP, like hair color changing
Cowden syndrome
-Autosomal dominant
-Gene that controls it is PTEN
-Increases risk of thyroid, breast and endometrial cancer
-Causes macrocephaly lipoma and fibroma
ATM
-Gene that encodes a protein that belongs to P 13/14 that helps maintain genomic integrity
-Mutations with this gene are associated with Ataxia telangiectasia (Autosomal recessive neurodegen disorder)
-Also mutations can increase risk of breast cancer
-Carriers can be identified within 1% of the population and should do partner testing
CHEK2
-Gene that provides instructions how to make checkpoint kinase 2 gene which acts as a tumor suppressor
-Mutation is high in polish population
Shows increased risk of cancer
-Prostate
-Breast
-Colon
3 mutations of CHEK2 gene
1100delC: Premature protein truncation
IVS2+1G>A Premature protein truncation
I157T: Substitutes isoleucine for threonine
TP53
Gene, basically guarantees you get cancer
-Avoid radiation at all cost
-Only can get MRI
PARP inhibitors
-Used BRCA 1/2
-Targets the mutation, killing cancer at the source (apoptosis)
-Used in ovarian cancer
Precision oncology
-Test tumor to find the drug most receptive to it
-Figure out the mutation
-Therapy is based on sample
Importance of identifying inherited cancer:
Prevention
Early diagnosis
Treatment
Quality of life
Importance of identifying inherited cancer: Prevention
-Preventive surgery and chemoprevention
Importance of identifying inherited cancer: Early diagnosis and detection
Mammograms and MRI
Importance of identifying inherited cancer: Treatment
Surgery and reconstruction, chemo and novel agents
Importance of identifying inherited cancer: QOL
Improves post surgery, risk reduction, reproductive health
Chemoprevention
-Tamoxifen(Soltamox), used in women with a 5 year risk of 1.67%
-Raloxifene (Evista)
-Prevents cancer
Tamoxifen: Cancer prevention
CYP2D6 is the main enzyme for converting tamoxifen to the active metabolite endofixen
-Within people’s genetic code there is variants with reduced or absent levels of this enzyme leading to severely diminished effects effects of Tamoxifen
-Can use genetic testing to find a drug that might work better rather than use a drug that wont work
CYP2C19
Gene responsible for the metabolism of Clopidogrel (Plavix)
-pts with affected genes are not able to metabolize plavix, putting them at a greater risk of blood clots
-Genetic testing can be used to make sure plavix will work
Ethical legal and social issues
-Benefits
Identification (High risk carriers, non carriers in families with known mutations)
Early detection
Relieves anxiety
Privacy: duty to warn, other family members of their risk
eMERGE
-Essentially it says issues of consent, contact, engagement and participation in genetic counseling to be considered before broader implementation of DNA sequence results into health care
-You cant force this on them
-People shared their genetic more often when they had a genetic provider than a non-genetic provider
Cardiac and genetic testing
Familial hypercholesterolemia
-Most common inherited cause of premature CHD is white people
-Essentially there is a gene to test if youre predisposed
