Patterns of Inheritance - 4 lectures Flashcards
1
Q
Multiple forms (alleles) of a gene in population (>1% of population)
A
polymorphism
2
Q
Probability that the offspring of a couple will express the genetic disease
A
recurrence risk
3
Q
person who approaches a physician or geneticist for a consultation
– this person may, or may not, be affected
A
consultand
4
Q
affected individual in the family who gains the attention of the physician due to a genetic condition
A
proband
5
Q
Mitochondrial (due to a mutation in a gene encoded by mitochondrial DNA) has what type of inheritance
A
non mendelian inheritance
6
Q
do you have father and son affected in X linked dominant disorders
A
nah
7
Q
difference between vertical and horizontal inheritance
A
vertical does not skip a generation (autosomal dominant) while horizontal does (autosomal recessive)
8
Q
Autosomal dominant disorders
A
NO HAM 2
neurofibromatosis type I, osteogenesis imperfects, huntingtons, familial hypercholesterolemia type IIa, achondroplasia, AIP, Marfan, Myotonic dystrophy
9
Q
Most pleiotropic phenotype of all unstable triplet repeat disorders
A
myotonic dystrophy
10
Q
define pleiotropic
A
one single gene mutation affecting multiple systems
11
Q
late onset
A
huntingtons, hemochromatosis, homocystinuria
12
Q
characteristics of myotonic dystrophy
A
wasting of the muscles, cataracts, heart conduction defects, endocrine changes, and myotonia
13
Q
myotonic dystrophy is mutation in what gene
A
DMPK gene
14
Q
Mutations in FGFR3 result in severe stunting of growth
A
achondroplasia
15
Q
Café-au-lait spots, Neurofibromas: swellings on the skin, lisch nodules in the iris of the eye
A
neurofibromatosis type I
16
Q
neurofibromin gene codes for
A
tumor suppressor protein
17
Q
mutation in NF-1 gene that has allelic heterogenity and can exhibit variable expressivity
A
neurofibromatosis type I
18
Q
what is allelic heterogenity
A
mutation can be found at different location/locus on the same gene
basically different mutations on the same locus cause same disease
19
Q
what is haplo-insufficiency
A
loss-of-function mutations in which half normal levels of the gene product result in phenotypic effects
20
Q
which autosomal dominant disorders exhibit haplo insufficiency
A
OAF 1
Osteogenesis imperfecta type I
AIP
familial hypercholesterolemia type IIa
21
Q
a mutant gene product interferes with the function of the normal gene product
A
dominant negative function
22
Q
which autosomal dominant disorders exhibit dominant negative function
A
MO
Marfan syndrome
Osteogenesis II, III, IV
23
Q
which autosomal dominant disorders exhibit gain of function
A
HA
Huntington’s
Achondroplasia
24
Q
prognosis for those who are homozygous for an autosomal dominant disorder
A
prognosis is worse than heterozygote and is usual lethal and is usually rare
25
what is it called if inheritance is only seen in one generation of the pedigree
horizontal inheritance
26
2/3 chance of being carrier applies to which mode of inheritance
autosomal recessive
27
what are the autosomal recessive disorders
How(2) Can(2) She(2) PET GoAts
Hemachromatosis, Homocystinuria, Cystic Fibrosis, Congenital deafness, Sickle Cell, SCIDS - ADA deficiency, PKU, Enzymes (most), Tay Sachs, Galactosemia, Alkaptonuria
28
2/3 rule doesn't apply to these autosomal recessive disorders and why
hemochromatosis and alkaptonuria
| because of delayed age of onset
29
phenotype of those with autosomal recessive disorder
loss of function mutation: so either reduced activity or complete loss of gene
30
What is the probability of a 30-year-old being homozygous for the normal form of an autosomal recessive disorder if both parents are carriers
33%
31
what does C282Y mutant allele mean in hemachromatosis
substitution of tyrosine with cysteine at amino acid position 282 (missense mutation)
32
Robin’s brother is identified to be a carrier of the C282Y allele of the HFE gene. What is probability of his children having the same mutant allele?
50%
33
if there are two different mutations on the same gene with two different phenotypic manifestations, is it allelic heterogenity?
nah because of TWO DIFFERENT MANIFESTATIONS
34
what happens when deficiency in ADA
build up of dATP --> toxic to B and T cells
| AKA SCIDS
35
2' deoxyadenosine ---> 2 deoxyinosine requires what enzyme
ADA = adenosine deaminase
36
Mr. R’s sister is identified to be a carrier of the mutant allele of the ADA gene. What is probability of her grandchildren having the same mutant allele?
25% (50% chance multiplied by 50% chance)
37
define pseudo autosomal dominance
an autosomal disease appearing in two or more generations giving the appearance of a dominant inheritance pattern
38
Factors that can increase incidence of an autosomal recessive trait in a population making it pseudo dominant
consanguinity, genetic isolation, heterozygote advantage (think sickle cell), assortative mating
39
carrier x affected gives appearance of
pseudo dominance inheritance
40
AB blood type is an example of what type of inheritance
codominance
41
person with type A blood can have what type of genotype
AA or AO
42
why are males considered hemizygous
if they have the one mutant X allele, then they have the X linked disease
43
region of chromosome that match
pseudoautosomal region
44
more common - X linked recessive or X linked dominant
X linked recessive
45
who are obligate carriers of X linked recessive diseases
mothers of affected son and daughters of affected males
46
male to male transmission seen in X linked recessive disorder?
nah
47
Recurrence risk for X-linked recessive disease with normal father and carrier mother
50% of daughters are carriers while other 50% are homozygous normal
50% of sons are affected while other 50% are normal
48
Recurrence risk for X-linked recessive disease with affected father and normal mother
all daughters are obligate carriers
| all sons are normal
49
Recurrence risk for X-linked recessive disease with affected father and carrier mother (SHIT IS RARE)
50% of daughters are affected while the other 50% are carriers
50% of sons are affected while the other 50% are homozygous normal
50
name the X linked recessive disorders
DoGS Really Like Hotdogs
```
Dystrophins (Duchenne and Becker)
Glucose 6 Phosphate dehydrogenase deficiency
SCIDS - IL2RG receptor defect
Red green color blindness
Lesch Nyhan
Hemophilia A and B
```
51
severe and milder form of dystrophy disorder
severe - duchenne (all the protein gone)
| mild - beckers (have some protein)
52
why do you hardly see male to male transmission of duchenne
has low reproductive fitness - males die before they reach reproductive age
53
phenotypes of person with Duchenne
enlarged calves and wasting of thigh muscles
54
big difference in hemophilia A and B
hemophilia A - deficiency of clotting factor VIII
| hemophilia B - deficiency of clotting factor IX
55
phenotype of person with hemophilia
severe bleeding after minor trauma, subcutaneous hematoma, hemarthrosis
56
what is locus heterogenity
present on two different loci/chromosome but present with the same phenotype
57
example of disease with locus heterogenity
SCIDS - one is on an autosome and one is on a sex chromosome
58
X linked SCIDS is a defect where
on the gamma chain of the receptor for several different interleukins (IL2RG)
also called gammaC cytokine receptors
59
problem with duchenne having a low reproductive fitness
very high chance of new mutation of this disease arising
60
what does it mean for a female to be a manifesting heterozygote
asymmetric X-inactivation/ skewed X inactivation - so a carrier female of a disease would show symptoms of the disease
some mutant cells are activated in most cells while normal cells are at a lower level
61
non lethal sex linked disease
red/green color blindness
62
X linked dominant disorders is more common in males or females
females
63
status of all daughters of affected male with X linked dominant disorders
they will be affected with the disease because they get the mutant allele X from padre
64
male to male transmission in X dominant?
nah
65
Recurrence risk for X-linked dominant disease of Affected Father with normal mother
all daughters will be affected
| all sons will be normal
66
Recurrence risk for X-linked dominant disease with Normal Father and affected mother
50% of sons and daughters will be affected
| 50% of sons and daughters will be normal
67
what are the X linked dominant disorders
Rett Syndrome, Vitamin D resistant rickets (hypophosphatemic rickets), incontinentia pigmenti
68
which X linked dominant disorders are lethal in males
rett syndrome and incontinentia pigmenti
69
why do females have less severe form of X linked dominant diseases
two copies of X - skewed X chromosome inactivation hence have more copies of normal allele in cell than the mutant allele
or disorder could be due to a germline mutation in the mother (germline mosaic)
70
how does incontinentia pigmenti manifest
as rashes or blisters in early life
later as patches of hyperpigmentation aka "marble cake appearance"
mental/retinal retardation
71
area of normal skin indicate what in incontinentia pigmenti
area where the normal X allele is present while hyperpigmented area is where the mutant allele is present
72
what are the Y linked mutations
SHE
various mutation on the SRY gene, H-Y histocompatibility antigen, hairy ears
73
who gets Y linked disorders and what does it cause
males and causes sterility sometimes hence are not passed on
74
if a father is affected with a Y linked disorder, what is the recurrence risk of his offsprings
all sons will be affected
| all daughters will be normal
75
what does non penetrance in an autosomal dominant disorder mean
individual has the disease genotype but not displaying disease phenotype buttttttt can still pass it off to offspring
76
disorder is fully penetrant if?
all people displaying disease genotype express disease phenotype/show manifestation of disease
77
reasons for incomplete penetrance
delayed age onset - for ex: huntingtons
78
what does 80% penetrance of a disorder mean
80% of those with disease will display disease phenotype while the other 20% will not
79
what is recurrence risk based on penetrance of a person with an autosomal dominant disease with 80% penetrance
first know that there is 50% recurrence risk of autosomal dominant disease
Of those 50%, 40% (50% of 80%) will display the disease phenotype while the other 10% will not
80
reasons for variable expression
random chance, genetic factors (modifier loci), environmental exposure
81
what is the mode of inheritance of hemochromatosis and why is it more severe in males than females
autosomal recessive disorder
less severe in females because they menstruate
82
why is there variable expression in individuals with xeroderma pigmentosum
it is more severe in those who are more frequently exposed to environmental UV radiation
83
what is the penetrance level in individuals affected with neurofibromatosis
there is high penetrance but variable expressivity
84
disorders that display pleiotropy
marfan syndrome and osteogenesis imperfecta
85
subluxation of lens, extremely tall, arachnodactyly, pectus excavatum, dilation of aorta are all features of?
Marfan
86
disorders that display locus heterogenity
osteogenesis imperfecta, sensorineural hearing impairment, retinitis pigmentosa, charcot marie tooth disease (AR, AD, X linked), SCID (AR and X linked), breast cancer
87
individual who inherits an abnormal allele from one parent and a different abnormal allele from the other parent hence being affected with the disease is said to be?
a compound heterozygote
88
recurrence risk for a new mutation
tends to be low
89
disease said to have hot spots for new mutations
osteogenesis imperfecta, Duchenne, Neurofibromatosis, achondroplasia, marfan
90
where do new mutation cells come from
gamete cells hence not present in parent's original genome
91
what is the genetic basis of new mutations
spermatogonia continually divide & sperm cells from older fathers may contain replication error mutations (point
mutations)
92
when there is no family history of a disease, what is the difference when one child is affected vs. multiple children?
one kid affected - new mutation
| multiple kids - germline (gonadal) mosaicism
93
diseases that have delayed age of onset
huntingtons, hemachromatosis, breast cancer, homocystinuria
94
A 23-year-old female is pregnant and has come for genetic counseling. Her father (50 years old) is diagnosed to have Huntington disease. What is her risk of having the disease? What is her risk of transmitting the mutant gene to her child?
her risk - 50%
| her offspring - 25%
95
recurrence risk of an offspring of a female with a mitochondrial inheritance disorder
100% because all children of affected mother will have disease because we get our mitochondria maternally
96
mitochondrial disorder with variable expression
heteroplasmy
97
severity of mitochondrial disorder is dependent on what
number of mitochondria that have the mutant gene
98
how does heteroplasmy occur in mitochondrial disorder
due to the unequal distribution of mutant and non mutant mitochondrial DNA
99
Thomas has MELAS. What is the recurrence risk of him passing it off to his offspring?
0% - males do not pass on their mitochondrial DNA
unless Thomas was once Tina jk
100
what are the mitochondrial diseases
MELAS (mitochondrial encephalopathy lactic acidosis and stroke like episodes)
Leber hereditary optic neuropathy
MERRF (Myoclonic epilepsy with ragged red muscle fibres)
101
how does leber hereditary optic neuropathy manifest
as progressive blindness at around age 20-30
102
Disorders with non-Mendelian/ unexpected inheritance patterns
• Digenic disorders
– Retinitis pigmentosa
• Imprinting
– Prader Willi syndrome
-- Angelman syndrome
• Triplet repeat disorders
– Huntington disease
– Myotonic dystrophy
– Fragile X syndrome (X-linked)
103
retinitis pigmentosa is a mutation in what
ROM1 and peripherin
104
what must happen in order for a person to have manifestations of retinitis pigmentosa
they must have a mutation both in ROM1 and peripherin - at least one mutant allele in both
105
what does it mean for a disorder to be digenic
mutations in two genes are additive and absolutely necessary in order to have the disorder
106
what does an imprinting disorder mean
some genes are active only from mother while some are active only from the father (methylation) - if something is messed up then there will be manifestation of the disease
107
what is the mutation in Prader Willi
Deletion of Paternal 15q11-13 (absence of SNRPN)
so SNRPN missing but mother's UBE3A present
108
manifestations of Prader Willi
obese, mental and developmental delay, hypotonia in infancy, failure to thrive, underdeveloped genatalia (micro-orchidism)
109
how do you detect Prader Willi
using FISH
110
what is uniparental disomy
two copies of a gene from one parent instead of one from each parent
111
what does restriction enzyme not cleave?
methylated DNA
112
reason for uniparental disomy in Prader Willy
meiotic I nondisjunction - homologous chromosomes fail to separate
113
what can be used to detect the cause of Prader Willy
polymorphic marker analysis
114
Deletion of maternal 15q11-13 (absence of active UBE3A gene)/ Uniparental disomy of paternal chromosome 15 (two copies of active SNRPN and absence of UBE3A gene)
Angelman Syndrome
115
Angelman is also called
happy puppet syndrome
116
manifestation of angelman syndrome
happy disposition, laugh inappropriately, severe mental retardation, seizures, puppet like posture of limbs
117
4 classes of triple repeat disorders
Fragile X, Fredlich ataxia, Huntingtons, Myotonic dystrophy
For Free Home Made Triplets
118
triple repeat at promoter region causing reduced expression
Fragile X - CGG
fraGGile
119
triple repeat at intron causing heterochromatin
Friedrich ataxia - GAA
Get A-taxi-A
120
triple repeat in coding part of gene causing polyglutamine expansion in protein
huntingtons - CAG
hunters in CAGe
121
triple repeat at 3' end (3 UTR) of gene
myotonic dystrophy - CTG
both myotonic and dystrophy have T so CTG
122
triple repeat explains this phenomenon - define the phenomenon
anticipation
individuals in more recent generation have higher number of triple repeats and disease more severe
123
In a family with myotonic dystrophy, a child is born with infantile myotonic dystrophy. The mother on examination is observed to have ptosis and mild facial weakness. The grandmother has bilateral cataracts and no demonstrable muscle weakness. The phenomenon in this family is/are
anticipation
124
manifestations of fragile X
anxiety, tantrum, poor muscle tone, Mental retardation, learning difficulties, prominent ears, elongated face, macro orchidism (enlarged testis)
125
fragile X is more severe when who transmits the disease
female
126
gene affected in fragile X
FMR1 gene methylated and silenced
127
what test is used to diagnose fragile X and what is seen
folate deficient medium - southern blotting - X chromosome show breakage
128
A study of the CFTR mutation in two separate families, revealed a codon deletion in one family and a missense mutation in the second family. This illustrates the concept of
allelic heterogenity
129
A study of the CFTR mutation in two separate families, revealed a codon deletion in one family and a missense mutation in the second family. A marriage occurred between members of these two families, and a child was born with CF. Which term describes this patient?
compound heterozygote
could also be allelic heterogenity
