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Genetic disorders > Genetics misc > Flashcards

Genetics misc Flashcards

1
Q

What is the incidence of autism (overall, boys, and girls)?

A

1/68 overall

1/42 boys

1/189 girls

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2
Q

What percentage of the risk for autism is genetic?

A

40-80%

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3
Q

What is the recurrence risk for autism?

A

6-8%, but may be as high as 19% (26% for males, 9.1% for females)

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4
Q

Why do genetic testing for autism?

A
  • Help provide better recurrence risk numbers
  • prevents unnecessary testing
  • help predict future medical complications, prognosis, and management
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5
Q

What is considered first-tier testing for non-sydromic autism?

A

Microarray

Fragile X

karyotype

hearing screening if there is language problems

lead levels

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6
Q

What is the male:female ratio for syndromic and non-syndromic autism?

A

1:1 male:female syndromic

>4:1 male:female non-syndromic

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7
Q

What makes a CNV likely pathogenic?

A

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

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8
Q

What is considered second tier testing for autism?

A

Rett

WES

specific gene testing

PTEN if macrocephalic (>/=95%)

Other (metabolic, EEG, neuroimaging)

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9
Q

What are characteristics of a channelopathy?

A

Intermittent, not always present

Episodic, have a bunch of episodes together

Normal between bouts/attacks

Triggers

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10
Q

What are some triggers for a channelopathy episode?

A

Hunger

fatigue

emotions

stress

exercise

diet

temperature

hormones

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11
Q

What is grip myotonia?

A

Can’t open hand quickly and it starts to cramp

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12
Q

What is muscle mounding?

A

When you hit a muscle with a hammer, it gets bigger

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13
Q

What is warm-up phenomenon?

A

Can do the action again after you rest or warm-up (related to myotonia)

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14
Q

What causes myotonia?

A

Hyperexcitable sarcolemma (channels doing too much)

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15
Q

What causes periodic paralysis?

A

Inexcitable sarcolema (channels so beat up they can’t do any more)

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16
Q

What are exercise tests used for?

A

Channelopathies

Myotonic disorders

to clarify phenotype adn suggest which channel is affected

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17
Q

What areas of the body can a channelopathy affect?

A

skeletal muscle

cardiac muscle

neuromuscular junction

peripheral nerve

CNS

(usually just one area is affected)

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18
Q

What are some common features of CMT?

A
  • 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
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19
Q

What questions should you ask if you suspect an inherited neuropathy?

A
  • 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
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20
Q

What will an electrophysiologic exam show?

A

Demyelinating vs axonal

CMTX shows moderate slowing

Inherited vs acquired (acquired has jagged peaks because myelination used to be normal but is now spotty)

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21
Q

Which CMT is demyelinating?

A

CMT1

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22
Q

Which CMT is axonal?

A

CMT2

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23
Q

What will neuropathy panels not pick up?

A

Del/dups

insertions

repeat expansion

epigenetic changes

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24
Q

What percent of neuropathy panels have a pathogenic or likely pathogenic variant identified?

A

~46% have a pathogenic or likely pathogenic variant identified

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25
Q

What percent of neuropathy panels don’t identify any cause?

A

43% don’t identify a cause

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26
Q

What is the etiolgy/embryology behind neurocutaneous syndromes?

A

Neuro and skin are both derived rom the ectoderm, so they are often affected together

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27
Q

Mutations in the ectoderm affect what?

A

Skin of the epidermis

Neuron of the brain

Pigment cells

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28
Q

What are some environmental causes of hearing loss?

A

Infection-prenatal (TORCHES, CMV, rubells, herpes), postnatal

ototoxic medications

acoustic trauma

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29
Q

Environmental causes account for what percentage of all hearing loss and what percentage of prelingual hearing loss?

A

25% of all hearing loss

50% of prelingual hearing loss

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30
Q

Of geneitc causes of pre-lingual hearing loss, what percentage is syndromic and what percentage is non-syndromic?

A

30% syndromic

70% non-syndromic

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31
Q

Of non-syndromic hearing loss, what percentage is inherited in an autosomal recessive fashion?

A

75-85%

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32
Q

Of autosomal recessive non-syndromic hearing loss, what percentage are due to connexin 26 (DFNB1)

A

50%

(~15% of all pre-lingual hearing loss)

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33
Q

How does autosomal dominant non-syndromic hearing loss present and what class of genes cause it?

A

Postlingual, progressive hearing loss

DFNA genes

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34
Q

What is the etiology behind connexin 26/DFNB1 hearing loss?

A

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
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35
Q

What is the carrier frequency of DFNB1/connexin 26/GJB2 mutations?

A

1 in 31-35 Caucasians

1 in 21-25 AJ

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36
Q

What are features that indicate hearing loss is not due to connexin 26 problems and you should not test for it?

A

Autosomal dominant inheritance (be aware of assortive mating where both parents are deaf, though)

There is hearing loss in only 1 ear

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37
Q

What are some things you should be aware of/ask about when working up a child for hearing loss?

A

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?
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38
Q

What percentage of retinoblastoma is heritable?

A

~40%

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39
Q

What percentage of RB1 mutations are de novo?

A

80%

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40
Q

What screening should be done for BAP1 mutations?

A

Exams for uveal melanoma starting at age 13

Skin melanoma exams starting at age 18

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41
Q

What are the benefits of testing and diagnosis hereditary eye diseases?

A

To know prognosis (will it progress?)

To have better management

To know other medical issues associated

To know recurrence risks

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42
Q

What is genetic heterogeneity?

A

same disease caused by different genes

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43
Q

What is allelic heterogeneity?

A

Same gene, but many different mutations that can cause disease

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44
Q

What is phenotypic heterogeneity?

A

Same gene, but different phenotype

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45
Q

What is clinical heterogeneity?

A

Same mutation, but different clinical consequences

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46
Q

What is the inheritance of cataracts?

A

Multifactorial

  • ~48% genetic
  • ~38% age
  • ~14% environment
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47
Q

What non-genetic factors have an impact on cataracts?

A

Non-what race

Light exposure

Female gender

Diabetes

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48
Q

What is the cause of congenital cataracts?

A

Mostly genetics

Can be from an intauterine infection (congenital rubella)

  • Unilateral less likely to be genetic
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49
Q

How does macular dystrophy change vision?

A

Loss of central vision

fuzzy vision

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50
Q

What gene greatly increases risk for age related macular degeneration and how much does it increase risk?

A

CFH gene

24 fold increased risk

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51
Q

What type is the most common form of glaucoma?

A

Primary open angle glaucoma

Chronic

Can use drugs to treat

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52
Q

How can primary acute closed angel glaucoma present?

A

May present with severe pain (may be worse in teh dare because the pupils dilate)

Probably needs surgery

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53
Q

What gene is associated with primary congenital glaucoma and how is it inherited?

A

CYP1B1

autosomal recessive

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54
Q

How is red-green, blue-yellow, and achromatopsia color blindness inherited?

A

red-green: X-linked

Blue-yellow: autosomal dominant

achromatopsia: autosomal recessive

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55
Q

What is the progression of retinitis pigmentosa?

A

First night blindness

Then loss of peripheral vision

Eventually loss of central vision (late)

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56
Q

How does choroidermia present?

A

Males present early with night blindness

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57
Q

What is keratoconus?

A

Conical shape of the cornia due to thinning and protrusion

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58
Q

Why is it important to treat strabismus?

A

Binocular vision develops early in life

  • If the lazy eye is severe, the child uses just one eye and does not develop binocular vision
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59
Q

What are the signs of retinal detachment?

A

sudden drop in visual acuity

flashes

increased floaters

painless usually

60
Q

What are some things you should ask about if you suspect Marfan syndrome?

A

Scoliosis

pectus

flat feet

pneumothorax

stiae not associated with marked weight change

family hx of sudden death

61
Q

What is the cystic fibrosis carrier frequency?

A

1 in 24 AJ

1 in 25 Caucasian

62
Q

What is the etiology of cystic fibrosis?

A

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
63
Q

How much CFTR function is needed to not have CF symptoms?

A

About 5-10% of gene function is needed

Milder mutations trump severe mutations

64
Q

What is the false negative rate for CF newborn screening and what is usually the cause of a false negative?

A

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

65
Q

If you are working up a patient for EDS, what features should make you think of another disorder besides EDS type 3?

A

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
66
Q

What is the best treatment for EDS type 3?

A

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

67
Q

What are some environmental factors that play a role in pancreatitis?

A

Alcohol

Tobacco

Sytemic illness

Trauma

Medications

Anatomical anomalies

Infection

68
Q

What makes up hemoglobin A?

A

two alpha chains

two beta chains

69
Q

What makes up hemoglobin A2?

A

2 Alpha chains

2 delta chains

70
Q

What makes up hemoglobin F (fetal)?

A

2 alpha chains

2 gamma chains

71
Q

What is the hemoglobin pattern of a typical newborn?

A

Alpha chains

decreasing amount of gamma chains

increasing amounts of beta chains

–>majority of Fetal, some increasing amounts of hemoglobin A

72
Q

What is the hemoglobin pattern of a typical adult?

A

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

73
Q

What kind of abnormality of sickle cell trait?

A

Structural (qualitative) abnormality leading to decreased oxygen affinity

74
Q

What kind of abnormality is a thalassemia?

A

Quantitative defect in alpha or beta chains

75
Q

What ethnicities have an increased carrier frequency of sickle cell?

A

African/African American

Mediterranean

Caribbean

South and Central American

Arab

East Indian

76
Q

What is HbBarts?

A

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

77
Q

What is hemoglobin H?

A

For beta chains together

See this with Alpha-thal

78
Q

What is the most common type of mutation in alpha thalassemia?

A

90% deletions

79
Q

In what population is a cis deletion of alpha genes more common and what is the consequence of this?

A

Asian populations are more likely to have cis deletions

Can lead to hydrops fetalis

80
Q

What are normal hemoglobin results on a newborn screen?

A

FA

(Fetal, A)

81
Q

What do FS results on newborn hemoglobin newborn screen mean?

A

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
82
Q

What do FSA hemoglobin results on newborn screen indicate?

A

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

83
Q

What do FAS hemoglobin newborn screen results indicate?

A

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

84
Q

What do FA + HbBarts hemoglobin newborn screen results indicate?

A

Fetal, A, HbBarts

  • Reduced amount of alpha chains because HbBarts is present

–>Alpha thalassemia trait OR Alpha Thalassemia Minor/HbH disease (3 gene mutation)

85
Q

What can an elevated amount of fetal hemoglobin in adults mean?

A

Can indicate a beta globin deletion (Beta-thal)

86
Q

What can an elevated amount of hemoglobin A2 indicate in an adult?

A

Can indicate beta-thal

87
Q

What are some psychosocial issues associated with hemoglobinopathies?

A

Living with a chronic disease

Pain

  • “look fine”
  • Accused of drug seeking

Parents missing work

Worseing health overtime

Holding a job/completing school

88
Q

What can cause a female to be affected by hemophilia?

A

Turner syndrome

Mosaicism

Consanguinity

89
Q

How is hemophilia treated?

A

Factor infusion

Can develop inhibitors (associated with intron 22 inversion)

90
Q

What type of hemophilia mutations are associated with an increased risk for devloping inhibitors?

A

Inversion 22 (Hemophilia A)

Large deletions

nonsense mutations

91
Q

What are some psychosocial issues related to hemophilia?

A

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
92
Q

What do blood clots in arteries lead to?

A

Stroke

heart attack

93
Q

What do blood clots in veins cause?

A

Deep vein thrombosis

pulmonary embolism

94
Q

What is a pulmonary embolism and what are the symptoms?

A

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
95
Q

What is the etiology of Factor V Leiden?

A

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
96
Q

Should you test for thrombophilia due to pregnancy loss or complications?

A

No

97
Q

How does being a poor metabolizer affect dosage?

A

Decrease dose for active drug

Increase dose if pro-drug

98
Q

How does being an intermediate metabolizer affect dosage?

A

Slightly decrease dose if an active drug

Slightly increase dose if a pro-drug

99
Q

What is an extensive metabolizer?

A

Normal metabilism, can use the regular dosage

100
Q

How does being an ultra metabolizer affect dosage?

A

Increase dose for an acitve drug

Decrease dose for a pro-drug

101
Q

What system is used to metabolize many different medications and where does this metabolism occur?

A

CYP gene system

  • system orginally for getting rid of toxins

Metabolism is in the liver

102
Q

What gene is mainly responsible for the metaboism of Warfarin and what are the genotypes?

A

CYP2C9

*3/*3 = poor metabolizer (4%)

*1/*3 = intermediate metabolizer (35%)

*1/*1 = extensive metabolizer (60%)

103
Q

A mutation in what gene can affect Warfarin metabolism and what are the genotype/phenotype?

A

VKOR

GG needs highest maintenance dose, poor metabolism (37%)

AG needs intermeiate maintenance dose (47%)

AA needs lowest maintenance dose (16%)

104
Q

What factors affect Warfarin metabolism?

A

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

105
Q

What kind of drug is Plavix and what gene is involved in metabolism of Plavix?

A

Pro-drug

CYP2C19

106
Q

What is a driver mutation?

A

Give a selective growth or survival advantage for cancer allow it to live and grow

107
Q

What is a passenger mutation?

A

A mutation that is just along for the ride, but does not give the cancer an advantage

108
Q

What is analytical validity?

A

Is it accurate (sensitivity, ability to correctly identify change)?

Is it precise (are the results reproducible)?

109
Q

What is clinical validity?

A

Are the test results associated with a real-world disease/condition?

110
Q

What is clinical utility?

A

Do the test results lead to management decisions for the patient that can improve outcome?

111
Q

What are the advantages of RNAseq + kinase capture for detecint kinase fusions?

A

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

112
Q

What is a genomics-enriched disease-based trial?

A

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

113
Q

What is a genomics-enriched basket trial?

A

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

114
Q

What is an exceptional responders trial?

A

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?

115
Q

How does MODY present/what does it look like?

A

It looks like Type 1 diabetes with a later, slower onset

116
Q

What are some limitations of GWAS?

A

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

117
Q

What are some benefits of GWAS?

A

Important for science

  • helps discover genes
  • Can reveal pathways
    • Can lead to teh development of new drugs
118
Q

What are some challenges for genetic disease therapy?

A

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?)

119
Q

What disease currently have enzyme replacement therapy available?

A

Fabry

Type 1 Gaucher

Pompe

Hurler

Hunter

Maroteaux-Lamy

120
Q

What are some risks of enzyme replacement therapy?

A

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
121
Q

What are some limitations of enzyme replacement therapy?

A

Cost

Insurance coverage

Efficacy

Blood-brain barrier (doesn’t improve intellectual disability)

  • Trials to look into intrethecal route injection to cross blood-brain barrier
122
Q

What are some methods for gene therapy?

A

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
123
Q

What are some methods to eliminate pathogenic mutations?

A

Exon skipping to restore reading frame

Deletion (induce exon-skipping/alternative splicing)

Correction (“gene editing”)

124
Q

What are some methods of somatic modification/tissue transplant?

A

Bone marrow transplant

Cord blood stem cell transplant

Liver transplant

125
Q

What are the advantages of tissue transplantation?

A

1 time treatment

May be curative for some disorders

126
Q

What are some limitations of tissue transplantation?

A

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)

127
Q

What does germline gene transfer involve?

A

Do gene transfer in gamete, zygote, or early embryo

(not really done)

128
Q

What is somatic gene transfer and what types are there?

A

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
129
Q

What is transduction?

A

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
130
Q

What needs to be considered when using a viral vector for transduction gene transfer?

A

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

131
Q

What is transfection?

A

Transfer of DNA, RNA, or oligonucleotides without a virus

  • Can be lipid based

Lower rates of transfer

Safer

132
Q

How can you increase function of partially-functional proteins?

A

Cofactor supplementation

  • Improve/encourage normal conformation

Interfere with chaperone molecules that degrade the mutant protein

133
Q

What are the most common types of childhood cancer?

A

Leukemia

CNS, brain, spinal cord tumors

Lymphoma

Skin cancer and melanoma

Soft tissue tumors

Germ cell tumors

Neuroblastoma

Bone cancer

renal cancer

retinoblastoma

134
Q

How is pediatric cancer different from adult cancer?

A

Fewer driver mutations

May not have a family history

135
Q

What percentage of pediatric cancers are due to a hereditary predisposition?

A

10-15%

136
Q

Why is it important to identify hereditary cancer predisposition syndromes?

A

Early screening –> early detection –> improved survival and treatment outcomes

Implications to family

137
Q

What can indicate a hereditary predisposition?

A
  • 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
138
Q

What can radial ray anomalies indicate?

A

Fanconi anemia

139
Q

What can hemihypertrophy indicate?

A

Beckwith-Wiedemann

140
Q

What can macrocephaly indicate?

A

PTEN mutation

141
Q

What can multiple cafe-au-lait spots indicate?

A

NF1

CMMR-1 (homozygous Lynch mutations)

142
Q

What can Shagreen patches indicate?

A

Tuberous sclerosis

143
Q

What can hypopigmentation indicate?

A

Tuberous sclerosis

144
Q

What counseling considerations are there for pediatric cancer?

A

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

145
Q

What is the detection rate for Duchenne/Becker muscular dystrophy?

A

93-96%

A negative results does not rule out a diagnosis

146
Q

How do you test for facio-scapulo-humeral muscular dystrophy?

A

Southern blot

Caused by smaller repeat size

Genetic disorders (2 decks)

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