Genetics misc Flashcards
What is the incidence of autism (overall, boys, and girls)?
1/68 overall
1/42 boys
1/189 girls
What percentage of the risk for autism is genetic?
40-80%
What is the recurrence risk for autism?
6-8%, but may be as high as 19% (26% for males, 9.1% for females)
Why do genetic testing for autism?
- Help provide better recurrence risk numbers
- prevents unnecessary testing
- help predict future medical complications, prognosis, and management
What is considered first-tier testing for non-sydromic autism?
Microarray
Fragile X
karyotype
hearing screening if there is language problems
lead levels
What is the male:female ratio for syndromic and non-syndromic autism?
1:1 male:female syndromic
>4:1 male:female non-syndromic
What makes a CNV likely pathogenic?
de novo
inherited from an affected parent
overlaps with known disease associated region
gene rich area
deletion more likely to be pathogenic
>3mb more likely to be pathogenic
What is considered second tier testing for autism?
Rett
WES
specific gene testing
PTEN if macrocephalic (>/=95%)
Other (metabolic, EEG, neuroimaging)
What are characteristics of a channelopathy?
Intermittent, not always present
Episodic, have a bunch of episodes together
Normal between bouts/attacks
Triggers
What are some triggers for a channelopathy episode?
Hunger
fatigue
emotions
stress
exercise
diet
temperature
hormones
What is grip myotonia?
Can’t open hand quickly and it starts to cramp
What is muscle mounding?
When you hit a muscle with a hammer, it gets bigger
What is warm-up phenomenon?
Can do the action again after you rest or warm-up (related to myotonia)
What causes myotonia?
Hyperexcitable sarcolemma (channels doing too much)
What causes periodic paralysis?
Inexcitable sarcolema (channels so beat up they can’t do any more)
What are exercise tests used for?
Channelopathies
Myotonic disorders
to clarify phenotype adn suggest which channel is affected
What areas of the body can a channelopathy affect?
skeletal muscle
cardiac muscle
neuromuscular junction
peripheral nerve
CNS
(usually just one area is affected)
What are some common features of CMT?
- frequent tripping, falling, clumsiness
- recurrent ankle injuries
- slow running, not very athletic or lsot athleticism when older
- difficulty jumping
- hard to find shoes that fit
- funny looking feet (high arch, flat feet, thin ankle)
- champagne bottle legs
- asymmetry
- peroneal muscle atrophy
- gait disturbance (flapping, walk like a duck)
- leg cramps as a child
- accelerated fatigue when walking short distances
- distal weakness
- sensory loss without pain
- reduced reflexes
- enlarged palpable nerves in demyelinating forms
- foot drop
What questions should you ask if you suspect an inherited neuropathy?
- Foot deformities?
- wear special shoes?
- Not good at sports or lost the ability very quickly
- may not realize the extent of their symptoms
- genetic onset is very insidious vs acquired is a quick onset
What will an electrophysiologic exam show?
Demyelinating vs axonal
CMTX shows moderate slowing
Inherited vs acquired (acquired has jagged peaks because myelination used to be normal but is now spotty)
Which CMT is demyelinating?
CMT1
Which CMT is axonal?
CMT2
What will neuropathy panels not pick up?
Del/dups
insertions
repeat expansion
epigenetic changes
What percent of neuropathy panels have a pathogenic or likely pathogenic variant identified?
~46% have a pathogenic or likely pathogenic variant identified
What percent of neuropathy panels don’t identify any cause?
43% don’t identify a cause
What is the etiolgy/embryology behind neurocutaneous syndromes?
Neuro and skin are both derived rom the ectoderm, so they are often affected together
Mutations in the ectoderm affect what?
Skin of the epidermis
Neuron of the brain
Pigment cells
What are some environmental causes of hearing loss?
Infection-prenatal (TORCHES, CMV, rubells, herpes), postnatal
ototoxic medications
acoustic trauma
Environmental causes account for what percentage of all hearing loss and what percentage of prelingual hearing loss?
25% of all hearing loss
50% of prelingual hearing loss
Of geneitc causes of pre-lingual hearing loss, what percentage is syndromic and what percentage is non-syndromic?
30% syndromic
70% non-syndromic
Of non-syndromic hearing loss, what percentage is inherited in an autosomal recessive fashion?
75-85%
Of autosomal recessive non-syndromic hearing loss, what percentage are due to connexin 26 (DFNB1)
50%
(~15% of all pre-lingual hearing loss)
How does autosomal dominant non-syndromic hearing loss present and what class of genes cause it?
Postlingual, progressive hearing loss
DFNA genes
What is the etiology behind connexin 26/DFNB1 hearing loss?
GJB2 mutations-encodes the gap junction protein connexin 26
- Connexin 26 is a transmembrane protein that helps create gap junctions and allow for ion transfer between cells and quick communication
- Mutations knock out the channels so cells can’t communicate
What is the carrier frequency of DFNB1/connexin 26/GJB2 mutations?
1 in 31-35 Caucasians
1 in 21-25 AJ
What are features that indicate hearing loss is not due to connexin 26 problems and you should not test for it?
Autosomal dominant inheritance (be aware of assortive mating where both parents are deaf, though)
There is hearing loss in only 1 ear
What are some things you should be aware of/ask about when working up a child for hearing loss?
How is it inerited (be aware of assortive mating where both parents are deaf)
Is the child dysmorphic, have birth defects, or ear abnormalities?
- is it syndromic or non-syndromic?
What percentage of retinoblastoma is heritable?
~40%
What percentage of RB1 mutations are de novo?
80%
What screening should be done for BAP1 mutations?
Exams for uveal melanoma starting at age 13
Skin melanoma exams starting at age 18
What are the benefits of testing and diagnosis hereditary eye diseases?
To know prognosis (will it progress?)
To have better management
To know other medical issues associated
To know recurrence risks
What is genetic heterogeneity?
same disease caused by different genes
What is allelic heterogeneity?
Same gene, but many different mutations that can cause disease
What is phenotypic heterogeneity?
Same gene, but different phenotype
What is clinical heterogeneity?
Same mutation, but different clinical consequences
What is the inheritance of cataracts?
Multifactorial
- ~48% genetic
- ~38% age
- ~14% environment
What non-genetic factors have an impact on cataracts?
Non-what race
Light exposure
Female gender
Diabetes
What is the cause of congenital cataracts?
Mostly genetics
Can be from an intauterine infection (congenital rubella)
- Unilateral less likely to be genetic
How does macular dystrophy change vision?
Loss of central vision
fuzzy vision
What gene greatly increases risk for age related macular degeneration and how much does it increase risk?
CFH gene
24 fold increased risk
What type is the most common form of glaucoma?
Primary open angle glaucoma
Chronic
Can use drugs to treat
How can primary acute closed angel glaucoma present?
May present with severe pain (may be worse in teh dare because the pupils dilate)
Probably needs surgery
What gene is associated with primary congenital glaucoma and how is it inherited?
CYP1B1
autosomal recessive
How is red-green, blue-yellow, and achromatopsia color blindness inherited?
red-green: X-linked
Blue-yellow: autosomal dominant
achromatopsia: autosomal recessive
What is the progression of retinitis pigmentosa?
First night blindness
Then loss of peripheral vision
Eventually loss of central vision (late)
How does choroidermia present?
Males present early with night blindness
What is keratoconus?
Conical shape of the cornia due to thinning and protrusion
Why is it important to treat strabismus?
Binocular vision develops early in life
- If the lazy eye is severe, the child uses just one eye and does not develop binocular vision
What are the signs of retinal detachment?
sudden drop in visual acuity
flashes
increased floaters
painless usually
What are some things you should ask about if you suspect Marfan syndrome?
Scoliosis
pectus
flat feet
pneumothorax
stiae not associated with marked weight change
family hx of sudden death
What is the cystic fibrosis carrier frequency?
1 in 24 AJ
1 in 25 Caucasian
What is the etiology of cystic fibrosis?
CFTR channel transports ions/chloride to the outer part of the cell
- other ions and water follow
- This balances the electrolyte concentration in mucus
When the CFTR channel doesn’t work properly, water doesn’t flow out of the cell like it should
- this creates sticky mucus that can’t clean and be cleared as it should
How much CFTR function is needed to not have CF symptoms?
About 5-10% of gene function is needed
Milder mutations trump severe mutations
What is the false negative rate for CF newborn screening and what is usually the cause of a false negative?
5-10% are false negatives
False negatives are usually pancreatic sufficient (milder cases)
Many of these babies have meconium ileus and will be tested for CF anyway
If you are working up a patient for EDS, what features should make you think of another disorder besides EDS type 3?
Neurologicl symptoms
- developmental delay
- autism
- seizures
- –>hypermobility is probably from hypotonia in these cases
Marfanoid habitus
- do an echo to make sure it’s not Marfan or something serious!
- dilated aortic root
What is the best treatment for EDS type 3?
Psychological counseling with cognitive bahvioral therapy
- This can be difficult psychosocially
- EDS patients have usually been told for years that they are faking their symptoms
- All they want is a diagnosis
- You finally give them a diagnosis, but then tell them to get psychological counseling…they may not like this/get defensive
Physical therapy can sometimes help
Pain management with NSAIDS or anticonvulsants can help
Antidepressants at low doses help with fibromyalgia
What are some environmental factors that play a role in pancreatitis?
Alcohol
Tobacco
Sytemic illness
Trauma
Medications
Anatomical anomalies
Infection
What makes up hemoglobin A?
two alpha chains
two beta chains
What makes up hemoglobin A2?
2 Alpha chains
2 delta chains
What makes up hemoglobin F (fetal)?
2 alpha chains
2 gamma chains
What is the hemoglobin pattern of a typical newborn?
Alpha chains
decreasing amount of gamma chains
increasing amounts of beta chains
–>majority of Fetal, some increasing amounts of hemoglobin A
What is the hemoglobin pattern of a typical adult?
Alpha chains
Steady amounts of beta chains
Very slightly increasing amounts of delta chains
Very little bit of gamma chains
–>Majority HbA, some A2, a little F
What kind of abnormality of sickle cell trait?
Structural (qualitative) abnormality leading to decreased oxygen affinity
What kind of abnormality is a thalassemia?
Quantitative defect in alpha or beta chains
What ethnicities have an increased carrier frequency of sickle cell?
African/African American
Mediterranean
Caribbean
South and Central American
Arab
East Indian
What is HbBarts?
4 gamma chains together
This is NOT the same things Barts fetalis, but is seen with Barts fetalis
May see this on newborn screen for alpha-thal
What is hemoglobin H?
For beta chains together
See this with Alpha-thal
What is the most common type of mutation in alpha thalassemia?
90% deletions
In what population is a cis deletion of alpha genes more common and what is the consequence of this?
Asian populations are more likely to have cis deletions
Can lead to hydrops fetalis
What are normal hemoglobin results on a newborn screen?
FA
(Fetal, A)
What do FS results on newborn hemoglobin newborn screen mean?
Fetal hemoglobin, HbS (sickle cell) hemoblobin
Indicates there are no functioning beta chains. Could be:
- Sickle cell disease (HbSS)
- Sickle/B- thal
- Sickle cell disease (HbSS) + hereditary persistance of fetal hemoglobin
What do FSA hemoglobin results on newborn screen indicate?
Feta, HbS (sickle cell), hemoglobin A
- More sickle cell beta chains than normal beta chains, so there is a decreased amount of beta chains
–>Sickle cell/B+ thalassemia
What do FAS hemoglobin newborn screen results indicate?
Fetal, HbA, HbS (sickle cell)
- Sickle cell beta chains present, but normal amount of beta chains because there is more HbA than HbS
–>Sickle cell trait
What do FA + HbBarts hemoglobin newborn screen results indicate?
Fetal, A, HbBarts
- Reduced amount of alpha chains because HbBarts is present
–>Alpha thalassemia trait OR Alpha Thalassemia Minor/HbH disease (3 gene mutation)
What can an elevated amount of fetal hemoglobin in adults mean?
Can indicate a beta globin deletion (Beta-thal)
What can an elevated amount of hemoglobin A2 indicate in an adult?
Can indicate beta-thal
What are some psychosocial issues associated with hemoglobinopathies?
Living with a chronic disease
Pain
- “look fine”
- Accused of drug seeking
Parents missing work
Worseing health overtime
Holding a job/completing school
What can cause a female to be affected by hemophilia?
Turner syndrome
Mosaicism
Consanguinity
How is hemophilia treated?
Factor infusion
Can develop inhibitors (associated with intron 22 inversion)
What type of hemophilia mutations are associated with an increased risk for devloping inhibitors?
Inversion 22 (Hemophilia A)
Large deletions
nonsense mutations
What are some psychosocial issues related to hemophilia?
Lifelong physical, psychological, financial, and employment challenges
Coping with a chronic health condition
Employment (multiple hospitalization, need for good insurance)
Planning life and job selection around health concerns
Parental concerns
- helping child lead a an active life
- coping of “loss” of normal child
- impact on siblings
What do blood clots in arteries lead to?
Stroke
heart attack
What do blood clots in veins cause?
Deep vein thrombosis
pulmonary embolism
What is a pulmonary embolism and what are the symptoms?
When a blood clot breaks loose from the leg and travels to the lung
Symptoms:
- chest pain with deep breathing
- new onset of shortness of breath
- Unexplained back or shoulder pain
- Cougging up blood
- fast heart beat
- fainting
- may be asymptomatic
What is the etiology of Factor V Leiden?
Factor V is resistant to activated protein C
- Protein C normally inactivates Factor V so the clot stops forming
- With Factor V Leiden, it takes longer for the formation of the clot to stop
Should you test for thrombophilia due to pregnancy loss or complications?
No
How does being a poor metabolizer affect dosage?
Decrease dose for active drug
Increase dose if pro-drug
How does being an intermediate metabolizer affect dosage?
Slightly decrease dose if an active drug
Slightly increase dose if a pro-drug
What is an extensive metabolizer?
Normal metabilism, can use the regular dosage
How does being an ultra metabolizer affect dosage?
Increase dose for an acitve drug
Decrease dose for a pro-drug
What system is used to metabolize many different medications and where does this metabolism occur?
CYP gene system
- system orginally for getting rid of toxins
Metabolism is in the liver
What gene is mainly responsible for the metaboism of Warfarin and what are the genotypes?
CYP2C9
*3/*3 = poor metabolizer (4%)
*1/*3 = intermediate metabolizer (35%)
*1/*1 = extensive metabolizer (60%)
A mutation in what gene can affect Warfarin metabolism and what are the genotype/phenotype?
VKOR
GG needs highest maintenance dose, poor metabolism (37%)
AG needs intermeiate maintenance dose (47%)
AA needs lowest maintenance dose (16%)
What factors affect Warfarin metabolism?
CYP2CP has up to 15% effect
VKOR has up to 25% effect
Age, sex, weight have 10-20% effect
Other factors (diet, vitamin K levels, other drugs) have up to 40% effect
–>Other factors beside genetics have more of an effect on metabolism
What kind of drug is Plavix and what gene is involved in metabolism of Plavix?
Pro-drug
CYP2C19
What is a driver mutation?
Give a selective growth or survival advantage for cancer allow it to live and grow
What is a passenger mutation?
A mutation that is just along for the ride, but does not give the cancer an advantage
What is analytical validity?
Is it accurate (sensitivity, ability to correctly identify change)?
Is it precise (are the results reproducible)?
What is clinical validity?
Are the test results associated with a real-world disease/condition?
What is clinical utility?
Do the test results lead to management decisions for the patient that can improve outcome?
What are the advantages of RNAseq + kinase capture for detecint kinase fusions?
Target kinase in the transcriptome?
Can capture a lot of different fusions
Can be used to detect other things (fusions, mutations, gene expression)
Can be quantitative
What is a genomics-enriched disease-based trial?
Have a group of people with a specific disease
Separate them out into groups based on the pathway-cause of their disease
Treat based pathway
What is a genomics-enriched basket trial?
Have a group of people with different types of rare cancer
Separate them out based on the driver mutation/pathway (may have a different type of cancer, but they have the same driver mutation)
Treat based on the pathway/driver mutation
What is an exceptional responders trial?
Have an exceptional responder to a certain drug that didn’t work for most people
Do genomic assessment to determine why they are exceptional responders?
How does MODY present/what does it look like?
It looks like Type 1 diabetes with a later, slower onset
What are some limitations of GWAS?
Mostly European populations
Dependent on the data collected
- Data is a snapshot in time, you don’t know if they developed some disease later in life
- Definitions of diseases were different then (ex/ schizophrenia)
Most SNPs have a very small effect on risk
Show association only, not causation
Replication is an absolute must
Need large populations and control groups
What are some benefits of GWAS?
Important for science
- helps discover genes
- Can reveal pathways
- Can lead to teh development of new drugs
What are some challenges for genetic disease therapy?
Timing of therapy
- can we diagnose them early enough for therapy to be effective?
- How long will they need to be treated?
Location of gene therapy
- Is the gene needed in one tissue (muscle) or every tissue?
- Is it needed intracellularly or extracellularly?
Mechanism of the mutation
- Can you just replace the wild-type gene (AR conditions)
- Does the mutation have harmful effects (dominant-negative)
- in order to treat it, you need to get rid of/fix the bad copy
Amount of gene expression needed
- AR coniditions usually only need ~10% enzyme activity
What is a meaningful effect and who decides if it’s meaningful?
Long-term side effects
Informed consent (is it really informed?)
What disease currently have enzyme replacement therapy available?
Fabry
Type 1 Gaucher
Pompe
Hurler
Hunter
Maroteaux-Lamy
What are some risks of enzyme replacement therapy?
Infusion reactions
- fever, chills, rash, pruritis etc
- Allergic reaction
- can be life-threatening
- usually develop over time
Frequent IV access
- Need a port usually
- Increased risk of infection
What are some limitations of enzyme replacement therapy?
Cost
Insurance coverage
Efficacy
Blood-brain barrier (doesn’t improve intellectual disability)
- Trials to look into intrethecal route injection to cross blood-brain barrier
What are some methods for gene therapy?
Gene augmentation/addition
- for AR conditions due to loss of function mutations
Elimination of pathogenic mutations
- For dominant gain of function mutations
Targeted inhibition of gene expression “gene silencing”
- For dominant gain of function mutations
Targeted killing of specific cells
- For cancer mainly
What are some methods to eliminate pathogenic mutations?
Exon skipping to restore reading frame
Deletion (induce exon-skipping/alternative splicing)
Correction (“gene editing”)
What are some methods of somatic modification/tissue transplant?
Bone marrow transplant
Cord blood stem cell transplant
Liver transplant
What are the advantages of tissue transplantation?
1 time treatment
May be curative for some disorders
What are some limitations of tissue transplantation?
Need to find a match
Risky chemotherapy and/or surgery
Risk of non-engraftment/rejection
Lifetime need for immune suppression (except for complete bone marrow transplant)
What does germline gene transfer involve?
Do gene transfer in gamete, zygote, or early embryo
(not really done)
What is somatic gene transfer and what types are there?
Modification of specific cells/tissues
In-vivo
- for cells that can’t be obtained or grown in culture
- brain cells
In vitro
- Extract cells, modify in culture, reintroduce cells to the body
- Hematopoietic or skin cells
What is transduction?
Transfer genes into body using a virus
High rates of gene transfer
Can be integrating
- gene inserted into the genome
- long-lasting expression
- Have to make sure it gets inserted in the right spot
- greater risk
Can be non-integrating
- Deposit gene extra-chromosomally
What needs to be considered when using a viral vector for transduction gene transfer?
Integrating vs non-integrating
Tropism (what cells, tissues, and species will the virus work with)
Size of gene that can be carried
Length of expression
Pre-existing reacting antibodies to the viral vector
Viral virulence
What is transfection?
Transfer of DNA, RNA, or oligonucleotides without a virus
- Can be lipid based
Lower rates of transfer
Safer
How can you increase function of partially-functional proteins?
Cofactor supplementation
- Improve/encourage normal conformation
Interfere with chaperone molecules that degrade the mutant protein
What are the most common types of childhood cancer?
Leukemia
CNS, brain, spinal cord tumors
Lymphoma
Skin cancer and melanoma
Soft tissue tumors
Germ cell tumors
Neuroblastoma
Bone cancer
renal cancer
retinoblastoma
How is pediatric cancer different from adult cancer?
Fewer driver mutations
May not have a family history
What percentage of pediatric cancers are due to a hereditary predisposition?
10-15%
Why is it important to identify hereditary cancer predisposition syndromes?
Early screening –> early detection –> improved survival and treatment outcomes
Implications to family
What can indicate a hereditary predisposition?
- Tumor type
- bilateral tumors
- multiple primary cancers (make sure it’s not due to treatment of first cancer)
- Dysmorphology, 2+ congenital anomalies, cutaneous characteristics
- radial ray anomalies
- hemihypertrophy, organomegaly
- genital abnormalities
- macrocephaly
- Family history
What can radial ray anomalies indicate?
Fanconi anemia
What can hemihypertrophy indicate?
Beckwith-Wiedemann
What can macrocephaly indicate?
PTEN mutation
What can multiple cafe-au-lait spots indicate?
NF1
CMMR-1 (homozygous Lynch mutations)
What can Shagreen patches indicate?
Tuberous sclerosis
What can hypopigmentation indicate?
Tuberous sclerosis
What counseling considerations are there for pediatric cancer?
Testing minors
- Usually diagnostic because the child already has cancer
- Consent/assent-parents may want testing but child/teen may not
- Do it if there is a pediatric cancer risks, and/or if screening starts in childhood
- difficult because BRCA & LS aren’t associated childhood cancers, but biallelic mutations are
Clinical utility of tesing
- Have to consider case by case, syndrome by syndrome
How do you screen whn no mutation is found?
Risks may not be known with certain syndromes
What is the detection rate for Duchenne/Becker muscular dystrophy?
93-96%
A negative results does not rule out a diagnosis
How do you test for facio-scapulo-humeral muscular dystrophy?
Southern blot
Caused by smaller repeat size
