L6, L7, L8, L9 Patterns of Inheritance Flashcards
1
Q
define gene
A
sequence of DNA that codes for protein, includes the regulatory regions
2
Q
what is a regulatory region?
A
a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism.
3
Q
define locus
A
location of a gene on a chromosome
4
Q
define allele
A
different version of a gene that occur on a locus - defines the amino acid or base sequences
5
Q
define polymorphism
A
multiple alleles of a gene in population - when an allele is found in > 10% of population and has a normal function - like different blood types
6
Q
define homozygote
A
has same alleles at a locus
7
Q
define heterozygote
A
has different alleles at a locus
8
Q
define dominant
A
requires only one copy of the mutation to produce disease
9
Q
define recessive
A
requires two copies of the mutation to produce disease
10
Q
what does recurrence risk mean?
A
the probability that the offspring of a couple will express the genetic disease.
for single gene disorders, it does not depend on the number of previously affected/unaffected offspring
DEPENDS ON THE MODE OF INHERTIANCE
11
Q
what is a pedigree
A
diagrammatic rep. of the family history
12
Q
what is a proband
A
AFFECTED individual in the family who has gone to a physician for a consultation
13
Q
what is a consultand?
A
a NOT AFFECTED individual who has gone to a physician for consultation
14
Q
define consanguinity
A
people who share the same blood - the relationship of 2nd cousin or closer!
15
Q
what are autosomal disorders?
A
when the mutant gene is present on autosomes
16
Q
what is x linked disorders?
A
when the mutant gene is present on sex chromosomes (x chromosome)
17
Q
are there any Y-linked disorders?
A
no transmission from Y gene, but there are certain traits we should be aware of.
18
Q
what are mitochondrial disorders?
A
when there is a mutation in a gene encoded by mitrochondrial DNA - NON-MENDELIAN
19
Q
define autosomal cominant
A
when the presence of one copy of the mutant allele on one chromosome is sufficient to cause disease
20
Q
in what state do autosomal dominant disorders manifest in
A
heterozygous state!
21
Q
what are characteristics of autosomal dominant disorders?
A
- affected child receives disease from affected parent
- does not skip generations (vertical inheritance)
- males and females are equally affected
- male to male - father to son transmission is seen
22
Q
define vertical inheritace
A
when a disorder does not skip generations - common with autosomal dominant disorders
23
Q
what are examples of autosomal dominant disorders?
A
- familial hypercholesterolemia - LDL receptor def.
- huntingtons disease - triple repeat expansion
- myotonic dystrophy - triple repeat expansion
- Marfan syndrome
- osteogenesis imperfecta
- achondroplasia
- neurofibromatosis type I
- acute intermittent porphyria
24
Q
what is myotonic dystrophy?
A
- mutation in the DMPK gene
- most pleiotropic phenotype of all unstable triple repeats disorders (affects multiple systems)
- characterized by wasting of muscle, heart conduction defects, endocrine changes, myotonia
25
what is achondroplasia?
mutation in FGFR3 - fibroblast growth factor receptor gene
- FGFR3 codes for transmembrane receptor that is involved in differentiation of cartilage to bone
- results in severe growth stunting
26
what is neurofibromatosis (NF1) aka von Recklinghausen disease
-mutation in neurofibriomin NF1 gene
-NF1 is cuased by different mutations in the NF1 gene --- allelic heterogeneity = same gene is mutant but different type of mutation in different families - single point vs. nonsense
-NF gene usually codes for tumor suppressor protein
-pts have neurofirbomas - painless swellings in skin and CN
HAS VARIABLE EXPRESSION - can be less or more severe
Cafe-au lait spots
neuro fibromas
Lisch nodules in iris of eye
27
what is osteogenesis imperfecta
DOMINANT NEGATIVE MODEL
- mutation in 1 allele of alpha 1 gene
- association of the triple helical molecules with atleast one mutant alpha 1, results in the degradation of collagen - 25% of collagen is normal and 75% of collagen is degraded
28
why do autosomal dominant mutations manifest in the heterozygous state?
1. Haplo-insufficiency
2. dominant-negative mutations
3. Gain-of-function
29
what is halo-insuffiency and what is an example?
- loss of function mutations in which half normal levels of the gene product results in disorder
- familial hypercholesterolemia - LDL receptors
- rarely there is an enzyme deficiency
30
what is dominant-negative mutations and what is an example?
a mutant gene product interferes with the function of the normal gene product
- osteogenesis imperfecta
- marfan syndrome
31
what is gain of function and what are examples?
result from increased levels of gene expression or the development of a new function of the gene product
- huntingtons disease
- achondroplasia
32
what is the homozygous state of autosomal dominant disorders?
much more severe or lethal like of OI
33
what state are autosomal recessive disorders expressed in?
homozygous state
34
who are carriers of the mutant gene in autosomal recessive disorders
both parents
35
in autosomal recessive disorders, carriers are what?
phenotypically normal
36
autosomal recessive disorders are usually seen in only one___
generation - horizontal inheritance = siblings are more commonly affected - males and females affected equally
37
is it possible to trace mutant allele transmission through the family without genetic testing
no! - why- because carriers are phenotypically normal!
38
most enzyme deficiencies are what mode of transmission?
autosomal recessive
39
what are common autosomal recessive disorders?
```
cystic fibrosis
MSUD
homocystinuria *
Sickle cell anemia
Phenylketouria
Tay-Sach's disease (Hexosaminidase A def.)
Congenital deafness
Hemochromatosis *
Galactosemia
```
40
what do loss of function mutations (molecular basis for autosomal recessive disorders) result in?
- reduced activity (hypomorph)
| - complete loss of gene product (null allele or amorph) = enzyme deficiencies
41
What is the mutations seen in Hemochromatosis?
C282 Y mutation of the HFE gene = most common
H63D and S65C are other mutations of the HFE gene
= ALLELIC HETEROGENEITY - same gene, different mutations possible to produce the same phenotypical manifestations!
42
when is the age of onset for hemochromatosis?
delayed age of onset
43
define pseudo-autosomal dominant
autosomal recessive condition present in individuals in 2 or more generations of a family - it looks like its following a dominant inheritance pattern = like sickle cell anemia in African Americans
an affected parent may have affected child - might see vertical transmission
high carrier frequency in pop
high consanguinity
44
what are the common explanations of pseudo-autosomal dominant disorders?
- high carrier frequency in population
- birth of an affected child to an affected individual
- genetically related (consanguineous) reproductive partner
45
what factors can increase the incidence of an autosomal recessive trait in a population (leading to pseudo-autosomal dominant)?
1. consanguinity
2. heterozygote advantage
3. genetic isolation - geo, religion, culture
4. assortative mating - people who are deaf marry other deaf people?
46
what is the pseudoautosomal region of a sex chromosome?
region of chromosomes that match - it is necessary to line up chromosomes correctly during meiosis
males are hemizygous
47
what are characteristics of X-linked recessive disorders?
- males require 1 copy of mutation (hemizygous) to be affected
- more common in males
- skipped generations
- affected father makes daughters carriers and then those girl transmit the mutation to their sons
- male to male transmission not seen
48
who are obligate carriers of mutant genes in x-linked recessive disorders?
the mothers of affected sons
| the daughters of affected males
49
what are common x-linked recessive disorders?
```
duchenne MD
Becker MD
Glucose 6 phosphate dehydrogenase def.
Hemophilia A and B
Lesch-Nyhan syndrome
Red-Green blindness
Rett syndrome
```
50
what is muscular dystrophy
Duchenne and Becker - both have mutations on dystrophin gene
Duchenne - males die young, don't really reproduce - "low reproductive fitness"
Becker - DO reproduce and can transmit mutation to sons
51
what does a G6PD deficiency result in?
hemolytic anemia on ingestion of drugs like priaquine, sulfa drugs
52
what is hemophilia A and B and what does it result in?
def. of clotting factor VIII because of mutation
| bleeding tendencies
53
what does Lesch-Nyhan syndrome result in?
HGPRT def. is problem = causes hyperuricemia and self mutilation
54
manifesting heterozygote in females with bleeding tendency is most commonly due to?
skewed x-inactivation (asymmaetic x inactivation)
if the skewed x inactivation occurs in liver - carrier may have factor VIII activity level below normal
symptoms are more mild in females compared to males
55
define skewed x inactivation?
the number of cells that contain the active mutant X are large compared to the cells that contain the active normal X
56
what is Rett Syndrome?
x linked disorder = lethal in males
affects females more often than males
because males usually die in utero or soon after birth
the mom does not have the manifestations of the disease - due to skewed x inactivation or due to a germline mutation in the female
57
what are characteristics of X-linked dominant disorders?
- does not skip generations
- more females are affected than males
- no male to male transmission***
- affected male transmits to ALL daughters, no sons
58
what are the two X-linked dominant diseases?
- vitamin D resistant Rickets (Hypophosphatemic rickets)
| - incontinentia pigmenti
59
what is incontinentia pigmenti?
- males in utero with disorder typically die in utero
- females are less severely affected
* expression is variabe
- manifests as rashes and blisters in early life
- later - patches of hyper pigmentation "marble cake appearance" of skin
- mental retardation in some
- retinal detachment in some
60
What are the genes on the Y chromosome in males involved in?
spermatogenesis - mutation = sterility = not passed on usually, but if it is = disease is only passed to sons because they have Y, not girls
61
what are examples of Y-linked inheritance?
- various mutations in the SRY genes
- H-Y histocompatibility antigen
- hairy ears
62
what is full penetrance
if all the people carrying the mutation express the manifestations of the disease
63
huntingtons disease has a ______ penetrace but a ____ age of onset
high
| delayed
64
how do you calculate recurrent risk based on penetrance?
penetrance of autosomal dominant disease x recurrent risk for every new child born to couple
/ 100
80% x 50% / 100 = 40% risk for next offspring when penetrance is 80%
65
define variable expression?
with individuals who inherit a mutant allele, there are some individuals who are severely affected and some who are mildly affected
66
what are diseases that show variable expression?
hemachromatosis - more severe in males (autosomal recessive)
xeroderm pigmentosum (autosomal recessive) - more severe in individuals exposed more frequently to UV radiation
osteogenesis imperfecta (autosomal dominant)
neurofibromatosis type I (autosomal dominant) - high penetrance
67
what does pleiotrophy mean?
disease causing mutation affects multiple organ systems
68
what are examples of pleiotropic diseases?
marfan syndrome - skeletal, joints, ocular, CV system etc.
Osteogenesis imperfecta - bone, sclera
69
what is locus heterogeneity?
mutations at different loci that cause the same disease phenotype
70
what are examples of diseases with locus heterogeneity?
osteogenesis imperfecta - defect in collagen, mutations of chromosome 17 or 7
sensorineural hearing impairment
retinitis pigmentosa
charcot marie tooth disease
breast cancer
71
define allelic heterogeneity
different mutations at the same locus cause the disease
72
what are diseases that display allelic heterogeneity?
neurofibromatosis 1
hemochromatosis
Cystic fibrosis
73
what are the characteristics of a new mutation?
- transmitted from unaffected parent to affect offspring
- maybe see an increase in age of father
- no family history of disease
74
what are examples of new mutation diseases?
neurofibromatosis
achondroplasia
Duchenne muscular dystrophy
osteogenesis imperfects
marfan syndrome
some x-linked recessive disorders
- couples risk of recurrence is low
75
define Germline moasicism
presence of 2 affected children with no family history - the mutation is present in a proportion of germline cels
76
define new mutation
single affected child with no family history
77
what are delayed age of onset diseases?
huntingtons disease
hemochromatosis
familial breast cancer
78
what are characteristics of mitochondrial inheritance?
mitochondria are inherited from mother
ALL offspring of an affected mother are affected - both male and female children
only females transmit the disease
affected father cannot transmit to children
79
what is responsible for the variable severeity of mitochondrial disorders?
heteroplasmy
unequal distribution of mutant and non-mutant mitochondrial DNA
80
what does the severity of the mitochondrial disorder depend on (heteroplasmy)?
the number of mitochondria that have the mutant gene
81
what are examples of mitochondrial diseases?
MELA (mitochondrial encephalopathy, lactic acidosis and stroke like symtoms
leber hereditary optic neuropathy
MERRF (myoclonic epilepsy with ragged red muscle fibers)
82
what are other diseases that lead to non-Mendelian inheritance patterns?
```
Digenic disorders
- retinitis pigmentosa
Imprinting
-Prader Willi syndrome
- Angelman syndrome
Triplet repeat disorders
-Huntingtons disease
Myotonic dystrophy
-Fragile X syndrome (x-linked)
```
83
what is a digenic disorder?
mutations in 2 genes (A,B) are necessary to produce the disorder
84
what is retinitis pigmentosa
disease of progressive visual impairment
| result of a mutation in 2 independent genes - ROM1 and Peripherin
85
explain impriting (parent of origin effects)
some genes, maternal loci (UBE3A) are active and for other genes paternal loci (SNRPN) are active
in normal, there are 2 SNRPN and 2 UBE3A - there is a methylation of 1 of each so you are left with 1 UBE3A and 1 SNRPN
86
what is Prader Willi syndrome?
absence of paternal SNRPN - micro deletion of 15q11-13
UBE3A is active
87
how is Prader willi syndrome detected?
FISH using specific probes against the region
88
what are the symptoms of Prader Willi syndrome?
obese
mental and developmental delay
underdeveloped genetalia
hypotonia in infancy, failure to thrive
89
what is uniparental disomy- Prader willi syndrome?
condition when a child has two copies of the maternal chromosome 15 - no SNRPN, 2 copies of UBE3A
trisomy 15 is not capatable with life - 1 of the chromosome are thrown out to preserve the zygote
90
how is uniparental disomy- Prader willi syndrome detected?
methylation analysis -
restiction enzyme does not cleave methylated DNA
restriction enzyme does cleave methylated DNA
91
what can be used to differentiate the cause of Prader Willi syndrome (due to microdeletion of paternal ch15 or due to uniparental disomy of materal ch15)?
polymorphic marker analysis - different color and letters for mom and dad to see what kid has
92
what is Angelman syndrome?
deletion of maternal 15q11-13 - no UBE3A gene, 2 copies of SNRPN = uniparental disomy of paternal chromosome 15
93
what are the symptoms of Angelman syndrome?
```
happy puppet syndrome
happy disposition, laugh inappropriately
severe mental retardation
seizures
puppet like posture of limbs
```
94
what are the 4 classes of triplet repeat?
fragile x syndrome
Friedrich ataxia
Huntingtons disease
Myotonic dystrophy
95
what sequences and location is Fragile x syndorme?
```
CGG
promoter region (5' end of the FMR1 gene)
```
96
what sequences and location is Friedrich ataxia?
GAA
| intron - results in abnormal mRNA processing
97
what sequences and location is Huntingtons disease?
CAG
coding region of the gene = polyglutamine expansion in the protein
CAG - codes for glutamine
98
what sequences and location is Myotonic dystrophy?
CTG
| 3' end (3' UTR) of the gene
99
what is responsible for the instability of repeats and then repeat size influence disease severity?
anticipation! - characteristic for triplet repeats!
| mutations probably in oogenesis or spermatogenesis
100
the ____ the number of repeats, the _____ the age of onset and then more _____ the disorder
greater
earlier
severe
101
in huntingtons disease, the disorder is more severe is transmitted from the ______
father
102
what are symptoms of fragile x syndrome?
```
mentral retardation
learning difficulties
prominent ears
elongated face
macro orchidism - big balls
```
shows anticipation in succesive generations
103
how is fragile x syndrome diagnosed?
southern blot analysis
| cytogenic test
