Exam 2: Lecture 28 Flashcards
(61 cards)
1
Q
What are single gene disorders (Mendelian disorders)
A
- mutations in single genes
- highly penetrant; follow mendelian inheritance patterns
2
Q
What are chromosomal disorders?
A
- structural or numerical alterations in chromosomes, involves several genes
- highly penetrant; can be sporadic or inherited
3
Q
What are complex multigenic disorders (multifactorial)
A
- caused by polygenic variants (polymorphisms) and environmental factors
- common diseases and traits ( diabetes, hypertension, height, weight)
4
Q
Single Gene disorder: Compare germ cell mutations and somatic mutations
A
- Germ cell mutation leads to inherited conditions
- Somatic mutation: associated with cancers and some congenital malformations
5
Q
Pathogenic variants vs benign variance
A
- pathogenic variants can cause disease
- benign variants do not cause a disease
6
Q
Describe a dominant negative inheritance
A
- if a mutated protein interferes with the function of the normal protein
- inheritance is often dominant
- ex. familial hypercholesterolemia
7
Q
Beta- Globin Gene (HBB)
A
- subunit of Hb
- Hb–> 2 alpha chains and 2 beta globin
- 3 exons; 146 AA; 900 variants that exist in HBB gene
- beta-thalacemia; HbS
- inhereted in autorecessive manner–> need 2 mutated alleles
8
Q
gene vs protein … gene is italicized and non- italicized is the protein
A
9
Q
HBB mutations and consequences
- mutation type and disease
A
1) Missense mutation ( Glu–> Val altering hydrophobic region …deoxygenation of RBC globin polymerizes leading to stiffening of RBC and sickling of RBC –> leading to immature rupture of RBC and later chronic anemia [ HgbSS ( Sickle Cell Disease)]
2)Non-se mutation: early stop codon at 39; causing decay of mRNA leading to no functional beta Globin (Beta Thalassemia major
- Beta Thalassemia: no beta globin produced, severe transfusion- dependent anemia
3) Non-coding region splice site mutation..could be misspliced mRNA leading to a premature stop codon; reduced beta globin production (some normal splicing may persist)
(Beta thalassemia intermedia)
- Beta thalassemia Intermedia- Reduced beta globin leads to moderate intermittent anemia
4) Indel: 4 nucleotide deletion in codon 41 leading to a frameshift and then a premature stop codon 19 codons downstream of the deletion ; shortened non-functional beta-globin–> complete loss of protein
- Beta thalassemia major: no beta globin; severe anemia.. assume homozygosity for the pathogenic variant
10
Q
Genetic Heterogeneity
A
- Refers to the presence of multiple, different genetic causes fir a single disease or condition
- ex. allelic heterogeneity and locus heterogeneity
11
Q
Allelic heterogeneity
A
- many different variants identified in a single gene can lead to the same of similar conditions
12
Q
Locus Heterogeneity
A
- variants in different genes may cause the same phenotype
13
Q
Other mutations: Trinucleotide repeat mutations
A
- amplified sequences like fragile X syndrome
14
Q
Other mutations: Structural variations
A
- copy number changes larger than 1Kb (amplifications/deletions)
15
Q
What are key factors in determining inheritance of pathogenic variants
A
- family history
- environmental factors and modifier genes
- variant location (autosomal vs sex chromosome)
- protein function and its physiological role
16
Q
Describe loss of function inheritance
A
- Loss of function is typically recessive because one functional copy of the gene is sufficient
- if a mutation completely inactivates a protein
- ex. PKU, Tay-Sachs disease (enzyme defects) or hemoglobinopathies (transport proteins)
17
Q
Describe gain of function inheritance
A
- if a mutation leads to a new or enhanced function
- gain of function is typically autosomal dominant because the altered protein interferes with normal cellular processes even when the normal copy is present
- ex. proto-oncogenes and Huntington disease
18
Q
What are other findings you see in pedigrees?
A
- denovo mutations
- advanced paternal
- gonadal mosaicism
- variable expressivity
-reduced penetrance
-later age of onset - skewed x -inactivation
19
Q
Describe reduced penetrance and later age onset affecting unaffected and mutation carriers
A
- Later age of onset: onset later, so individuals with pathogenic variant may not have symptoms if they are young
- Reduced penetrance: a certain percentage of people who have the pathogenic variant remain unaffected
20
Q
Gonadal mosaicism
A
- Scenario: both sons with different fathers and the same mom receive the disease
- son and daughter with different moms and the same dad have the disease
- Significance: the same parent denominator has the variant in germline, but not blood; future offspring are at risk of receiving the disease
21
Q
How can the penetrance and expression of a pathogenic variant be influenced?
A
- Modifier genes–> can enhance or suppress the expression of the primary disease- causing gene, leading to different clinical outcomes in individuals with the same genetic mutation
- environmental factors –> diet, air pollution, infections, toxins…. exposures to certain substances, lifestyle choices, and other environmental factors impact the severity or manifestation of a genetic disease
22
Q
What are patterns of autosomal inheritance in family history?
A
- younger age of onset
- consanguinity (cousins)
-unaffected parents - multiple family members with similar diseases and symptoms
23
Q
Wilson’s disease
A
- Pleiotropic (affects unrelated organ systems) autosomal recessive condition
- excess copper is toxic to the organs; accumulates typically in the liver, brain, and eyes
- other signs: cardiomyopathy, renal tubular dysfunction, arthritis, hepatomegaly, CNS disorders
- 6- 45 y/o are years of diagnoses
- cardinal signal: Kayser-Fleisher ring (a brown ring around the iris)
- C–> Cirrhosis; O–> Ocular Kayser- Fleisher ring ;P –> Psychiatric symptoms; P–> Parkinson’s like tremors ;E–> Elevated urinary copper ;R–> Recessive ATP7B
24
Q
Describe the role of ATP7B
A
- ATP7B- a P-type ATPase that transports copper ions across cellular membranes
- Copper transporter1 (CTR1) transports Cu into the cell; ATOX1 transports Cu inside the cell to ATP7B (Wilson ATPase)
- low cellular Cu–> ATP7B helps load Cu on apoceruloplasmin to form holoceruloplasmin in the trans-golgi network; leaves to cross the plasma membrane
- high cellular Cu: ATOX1 bound to Cu gives Cu to ATP7B in trans-golgi; excretes excess Cu in vesicles fuse with apical membrane and release it in the bile canaliculi (within liver)
- defects affect both, leading to toxic accumulation in the liver, brain, and other organs
25
What are diagnostic tests that can be done for Wilson's disease?
1) Serum ceruloplasmin--> low ( impaired copper transport)
2) 24hr urinary copper--> elevated (excess copper excretion)
3) Liver enzymes (ALT/AST)--> elevated (hepatic damage)
4) Genetic sequencing test --> homozygous pathogenic variant in ATP7BpHis 1069Gln
26
Describe haploinsufficiency inheritance
- type of loss of function variant
- if one normal copy of the gene is insufficient in generating enough protein for normal physiology the inheritance can be dominant
- ex. Marfan syndrome
27
Describe inclusion bodies in autosomal dominant Beta- Thalassemia
- blue cytoplasmic inclusions seen in the RBC precursors
28
What are treatments of Wilson Disease?
1) chelator drugs- D0 penicillamine and trientine induce renal excretion of copper
2) Zinc supplementation- blocks intestinal absorption
3) liver transplant when acute liver failure
4) gene therapy underway to introduce a functioning ATP7B
29
How to assess pedigrees
- look at affected generations (dominant is 2 generations)
- look at male vs female ( x linked because you have more males affected)
-
30
What are Gower's signs
- child has to use all 4s to get up and uses their hands on their lower limbs to get up off the floor to sit up
31
Describe Muscular dystrophy
- dystrophin mutation
- Normal: links intrnal cytosket
- lack of dystrophin leads to ongoing muscle damage; replacement of muscle fibers with scar tissue and fat
- some fibers experiecne atrophy and others hypertrophy; change in ise of teh muscle because of teh new placement of fat and scar tissue
- pseudocalf hypertrophy because of teh accumulation of fat
- DMD gene deletion ( located on x chromosome)--> prone to spontaneous mutation; de novo mutation
32
How can a patient without a history of muscular dystrophy have a de novo mutation? BMD
1) Maternal gonadal mosaicism--> increase risk of passing it on to future offspring
2) de novo mutation in the single oocyte
- Exon 45-47 deletion in DMD (on X chromosome); in frame deletion- leads to an atypical protein (partially functional- not as severe symptoms)
3) If you are to reproduce, 50% chance of passing it on to your offspring
33
How can a patient inherit muscle dystrophy? DMD
- frameshift mutation loss of functional, no protein
- Exon 45-50 deletion in DMD gene (on X chromosome)
34
What are dystrophinopathies?
- Duchenne Muscular Dystrophy (DMD)
- Becker Muscular Dystrophy (BMD)
- DMD- related Dilated Cardiomyopathy (DMD-related DCM)
35
Describe the role of dystrophin protein
- structure protein that links intracellular cytoskeleton to sarcoglycans and dystroglycans in the membranes and the extracellular matrix, providing mechanical stability and structure to muscle cell membrane during contraction
- expressed in skeletal, cardiac, smooth muscle, and in the brain
36
Compare DMD, BMD, and DMD-related DCM symptoms: Skeletal muscle involvement?
- DMD: Proximal
- BMD: Proximal
- DMD-related DCM: none
37
Compare DMD, BMD, and DMD-related DCM symptoms: Brain ?
- DMD: possible intellectual difficulties
- BMD: Possible intellectual difficulties
- DMD-related: none
38
Compare DMD, BMD, and DMD-related DCM symptoms: Mean age of onset?
- DMD: 3-5 yrs
- BMD: 12 yrs
- DMD-related DCM: males 20-40; females- later
39
Compare DMD, BMD, and DMD-related DCM symptoms: Speed of progression?
- DMD: Fast
- BMD: Slow
- DMD-related DCM: Males- fast; females- slow
40
Compare DMD, BMD, and DMD-related DCM symptoms: Wheelchair dependent?
- DMD: 12 years
- BMD: 27 years
- DMD-related DCM: N/A
41
Compare DMD, BMD, and DMD-related DCM symptoms: Mean life expectancy?
- DMD: 20s
- BMD: 40s
- DMD-related DCM: Males 1-2 yrs after onset; females 10 yrs after onset
42
Compare DMD, BMD, and DMD-related DCM symptoms: Cardiomyopathy?
- DMD: onset FOLLOWS skeletal muscle progression
- BMD: onset BEFORE skeletal muscle onset
- DMD-related DCM: yes
43
Compare DMD, BMD, and DMD-related DCM symptoms: Creatine Phosphokinase (CK)?
- DMD: > 10x normal
- BMD: > 5x normal
- DMD-related DCM: increased
44
Compare DMD, BMD, and DMD-related DCM symptoms: Muscle biopsy- immunochemistry?
- DMD: absent dystrophin
- BMD: reduced dystrophin
- DMD-related DCM: N/A
45
How do you treat dystrophinopathies?
- ACE inhibitors and beta blocker for cardiomyopathy
- corticosteroids to improve muscle strength and function in DMD and BMD
- no cure
- clinical trials are underway for gene therapy
46
What is the difference between DMD and BMD?
- DMD- Doesn't Make Dystrophin
- BMD- Badly Made Dystrophin (a truncated protein)
47
What are other multigenic disorders?
- heart disease, diabetes mellitus, hypertension, autoimmune diseases, etc.
- etiology: interactions between multiple genes and environments
- each gene polymorphism has a small effect and is low of penetrance
48
What are polygenic risk scores?
- combine info from multiple genetic variants
- currently being explored for clinical application
- offers potential risk stratification, screening, and personalized treatment
49
Marfan Syndrome
50
Tay- Sachs disease
51
Huntington Disease
52
Familial Hypercholesterolemia
53
Osteogenesis Imperfecta
54
What are the differences in autosomal dominant and autosomal recessive pedigrees?
- Dominant: phenotype appears in every generation; phenotypically normal parents do not transmit the condition to their offspring; males and females are equally likely to be affected; male to male transmission (distinguishes it from X linked); Heterozygotes' offspring have 50% risk to inherit the pathogenic variant
- Recessive: phenotype appears in a single generation; parents are typically unaffected; both males and females affected; consanguinity may be present; if both parents are heterozygous, 25% risk having an affected offspring and 50% chance of heterozygote and 25% homozygous wild alleles; unaffected sibling of an affected has 2/3 chance of being a carrier
55
Describe de novo mutations
- ne mutation in a sperm or egg cell that is involved in conception
- can explain an autosomal dominant condition with no family history
- occurs more frequently with advanced paternal age
- gonadal mosaicism aka germline mosaicism (de novo mutation in parent's germ cells) may allow unaffected parents to have affected offspring --> each offspring with the gonadal mosaicism may have an increased chance to inherit the pathogenic variant--> risk depends on the level of gonadal mosaicism, ... higher level means higher risk
56
Describe variable expressivity
- in some conditions not all individuals who have the pathogenic variant express the condition the same way
57
Describe skewed X inactivation
- some females with X linked recessive variants may be affected due to greater number of X chromosomes with wild type allele being inactivated
58
Fragile X syndrome
59
Why are individuals with confirmed mutation unaffected (without symptoms)?
- reduced penetrance
- later onset
60
How do Modifier Genes effects penetrance and expression of a pathogenic variant?
- genes can enhance or suppress the expression of the primary disease- causing gene, leading to different clinical outcomes in individual with the same genetic mutation
61
How do environmental factors effect penetrance and expression of a pathogenic variant?
- diet, air pollution, infections, toxins
- exposures to certain substances, lifestyle choices, and other environmental factors impact the severity or manifestations of genetic diseases
