Disease of Sex and Mendelian Inheritance Flashcards
What are modes of mendelian inheritance?
Autosomal dominant Autosomal recessive X-linked dominant X-linked recessive Mitochondrial Sex-limited and sex-influenced
What is penetrance?
the extent to which a particular gene or set of genes is expressed in the phenotypes of individuals carrying it, measured by the proportion of carriers showing the characteristic phenotype.
complete penetrance: individuals have the disorder and develop disorder symptoms
reduced penetrance: many individuals have the disorder mutation but do not develop disorder symptoms
Autosomal dominant has what sex ratio and transmission pattern? What is the likelihood of a child being affected if a father with normal homozygous mates with a mother who is heterozygotes for the dominant allele?
The disorder is observed in an equal number of females and males who are HETEROZYGOTES. The family pedigree is vertical. Transmission can be by mother or father.
Although homozygotes for some autosomal dominant disorders do occur (Noonan syndrome), homozygosity for an autosomal dominant allele is generally a genetic lethal.
There is a 50% chance (2 out of 4 children having a child with autosomal dominant disorder assuming complete penetrance. There is 50% chance of having a normal child.
What is proband/propositus?
a person serving as the starting point for the genetic study of a family (used especially in medicine and psychiatry).
What is the difference between Mendelian, polygenic, and multifactorial inheritance?
_____________explains phenotypes that depend on transmission of alleles at a single genetic locus
______________explains phenotypes that depend on transmission of alleles at multiple genetic loci
______________explains phenotypes that depend on transmission of alleles at polygenic loci and environmental factors
Mendelian inheritance
Polygenic inheritance
Multifactorial inheritance
A person with blood type A can either be AA or AO. What is the genotype and phenotype in this case?
Genotype is AA or AO.
Phenotype is blood type A.
Holandric is another term representing genes on the Y chromosome which is always transmitted by males
Y-linked
AB blood group is what type of Mendelian inheritance?
Co-dominance: two different alleles are expressed and seen together phenotypically.
The third (5’) base of the anticodon can typically pair with either member of the purine or pyrimidine pair in the codon as appropriate. In this example, the double-ringed G can pair with either a single-ringed U or C. What is this called?
wobble effect
This allows mRNA to be translated with fewer than the 64 tRNAs that would be required without wobble. Some wobble positions can pair with any of the four bases.
Inheritance pattern is a function of what?
phenotypic expression (TRAIT) not the allele
This refers to a situation when a disorder has multiple effects on the body. Marfan syndrome is an example.
Pleiotropy
-Marfan’s syndrome (autosomal dominant)
Mut. in FBN1 gene encodes fibrillin-1, glycoprotein constituent of connective.
effects skeletal, cardiovascular, nervous system, eyes and lungs
-Sickle Cell disease (autosomal recessive)
mut. in β-globin (HBB), protein component of hemoglobin HbA
Effects vascular system, kidney, heart, lung spleen
-Phenylketonuria (PKU) is autosomal recessive
Mut. in phenyalanine hydroxylase, metabolism of enzyme to c causes
mental retardation, hair and skin pigmentation, abnormal gait
and posture, and delayed growth
The severity of a disorder can vary greatly between individuals. Some people may have such a mild disorder that they do not know they have it until a severely affected child is born. Example: Marfan syndrome whereby a parent is tall and has long fingers, but one of this children is tall, has long fingers, and has serious cardiovascular defect. What does this situation refer to?
variable expressivity
Remember inheritance is function of the phenotypes (traits) expressed. We don’t know a person has a genetic mutation until we see symptoms stemming from the genetic mutation.
The affected children of an affected parent and an unaffected parent must be heterozygous in this type of mendelian inheritance.
Autosomal dominance
If both parents are heterozygous Dd x Dd, their
affected offspring have what chance of being DD if inheritance is autosomal dominant? What chance of being Dd?
2/3 for being DD
1/3 for being Dd
If both parents are heterozygous Dd x Dd, their affected offspring have what chance of being DD if inheritance is autosomal recessive?
O% because inheritance is autosomal recessive you need dd to be affected.
If both parents are heterozygous Dd x Dd, their offspring have what chance of being DD if inheritance is autosomal recessive?
1/4 for DD
This asks about offspring in general. Doesn’t matter what the inheritance is.
Upper limb cardiovascular syndrome, Marfan Syndrome, Multiple polyposis Coli, Neurofibromatosis I, Achondroplasia, and Retinoblastoma are example of what mendelian inheritance ?
Autosomal dominance
What is an outsider?
a person whose parents genotypes are not known
An affected outsider is assumed to be heterozygous (Dd).
All unaffected individuals are homozygous for the normal recessive allele dd.
What is the recurrence risk for an affected offspring if affected outsider mates with a normal individual?
1/2 or 50%
What is ascertainment bias?
Ascertainment bias is a systematic distortion in measuring the true frequency of a phenomenon due to the way in which the data are collected.
For true dominants the heterozygotes and homozygotes have indistinguishable phenotypes. What is an example of this and what deviates from this true dominance, what are examples?
True dominance: Huntington Disease
What is the difference and examples of pseudo-dominance, incomplete dominance, and co-dominance?
pseudo-dominance: More often, there is a difference in genotype/phenotype correlation (homozygotes are lethal and heterozygotes are short-limbed or affected with high levels of cholesterol)
- Achondroplasia – FGFR3 mutation (4p16.3)
- Familial hypercholesterolemia – LDLR gene (19p13.2)
Incomplete dominance – phenotype of heterozygous genotype is different from either homozygote (rec. or dom.)
and severity is intermediate
- HbAs is an example
Codominant – expression of each allele is detected in a phenotype; Neither allele can mask the other and both are expressed in the offspring and not in an “intermediate” form.
-ABO blood antigens
What is haploinsufficiency, give an example?
– loss of half the normal activity of protein causes disease
An example of this is seen in the case of Williams syndrome, a neurodevelopmental disorder caused by the haploinsufficiency of genes at 7q11.23.
What are dominant negative mutations?
mutant product
inhibits function of wild-type protein
osteogenesis imperfecta is an example where Type I collagen is affected. OI has significant clinical heterogeneity.
Locus heterogeneity. In locus heterogeneity, genes at more than one locus may cause the dis-
order. Example: Osteogenesis imperfecta whereby collagen a-1 (I) chain protein and colla-
gen a-2(I) chain protein are encoded by the COL1A1 gene on chromosome 17q21.3-q22 and
COL1A2 gene on chromosome 7q22.1, respectively (i.e., two separate genes located on dif-
ferent chromosomes). A mutation in either gene will cause osteogenesis imperfecta.
What are the special features of autosomal dominance that creates ambiguity?
Penetrance: failure of Dominant character to manifest when a person carries the responsible allele.
e.g. Triplet repeat amplification (need a certain amount of repeats to show the phenotype) which makes it seem like if the repeat number is low the person doesn’t have it at all
Anticipation: signs and symptoms of conditions tend to become more severe and appear at an earlier age in successive generations
Variable expressivity: wide range of expression (clinical heterogeneity) due to allelic variation or “genetic, environment or epigenetics background ”
i.e. Dominant conditions manifest different features of the syndrome
Penetrance nearly always refers to autosomal dominant conditions. Incomplete penetrance is when two individuals have the mutation but only 1 manifests the phenotype.
Penetrance is all or non- phenotype is present or not.
There is no intermediacy like there is in variable expressivity.
Café-au-lait spots to neurofibromas to cancer in neurofibromatosis type I or holoprosencephaly to facial dysmorphology to minor clefting in holoprosencephaly express degree of severity in phenotype termed?
variable expressivity
DMD is another example
Dystrophin gene – outcome of mutation effects
Duchenne Muscular Dystrophy – frameshifts, null allele
Becker Muscular Dystrophy – non-frameshifts , abnormal but present protein
X-linked Dilated Cardiomyopathy
DS is caused by a microdeletion of the DiGeorge chromosomal critical region (DGCR) on chromosome 22q11.2. 90% of DS individuals have a de novo deletion.
DiGeorge is autosomal dominant but can be pseudo autosomal recessive as a result of de novo mutations due to variable expressivity.
Neurofibromatosis is autosomal dominant but can be pseudo autosomal recessive due to variable expressivity.
Anticipation is one of the hall- marks of diseases caused by dynamic mutations. Anticipation means that a genetic disorder displays an earlier age of onset and/or a greater degree of severity in successive generations of the family pedigree. Anticipation is caused by?
new mutations or de novo mutations
Variable age of onset – Aut. Dom clinical manifestation may be age related as in early onset over generation (anticipation) or late onset (error in metabolism or deterioration of structures)
Sporadic cases occur in families because of a new mutation.
What is the requirement of parents for autosomal recessive disorder to be seen in an offspring?
Both parents are carriers (heterozygotes)
25% risk for affected child (rr)
50% risk for carrier child
25% risk for normal, non-carrier child
unaffected children have a 2/3 change of being a carrier Rr and a 1/3 of being normal RR
Need 2 mutant allelic genes for full clinical effect
New mutations and nonpenetrance not significant.
Horizontal pattern of inheritance (can skip a generation)
Sickle cell disease Cystic fibrosis Non-syndromic hearing loss Alpha-1 Antitrypsin Ashkenazi Jewish disorders Tay-Sachs disease Canavan disease Gaucher disease Fanconi anemia, type C Bloom syndrome Mucolipidosis type IV (Fabry's disease is X-linked)
These all have what type of inheritance?
autosomal recessive
Both parents are obligate heterozygous carriers whereby each parent carries one mutant allele and is asymptomatic (unless there is uniparental disomy or consanguinity, which increases the risk for autosomal recessive disorders in children). What is this inheritance?
autosomal recessive
What are the special features of autosomal recessive that creates ambiguity?
-Consanguinity
-Pseudo-dominance: mating between heterozygote and affected show vertical transmission
-Genetic heterogeneity: clinical trait can be inherited (Rec or Dom or sex) in various ways from different genes
-Compound heterozygote: two different mutations at the same locus that cause the same trait
E.g. cystic fibrosis, sensorineural hearing loss, β-tahlasemmia
What is the outsider rule for autosomal recessive?
Unaffected outsiders are assumed to be heterozygous normal
Consanguinity Increases the Incidence of Rare Autosomal Recessive Disorders. What is coefficient of relationship and coefficient of Inbreeding?
Inbreeding increases homozygosity: recessive traits (high) and dominant traits (low)
Coefficient of Relationship (COR). COR is the proportion of genes in common between two related individuals. COR is described by the equation below.
COR =1/2^(n-1)
Coefficient of Inbreeding (COI) or Homozygous by Descent. COI is the probability that an individual is homozygous at a locus as a result of consanguinity in his or her parents. COI is described by the equation below.
COI= (COR)1/2
COI= 1/2^(n+1)
What are communities that deliberately engage in consanguinity?
European Royal Families
Japanese Children after WWII
Amish Settlement
Why is pseudo-dominance a complication of autosomal recessive? Friedreich’s ataxia is an example of this.
Recessive allele acts dominant deleterious
mating between heterozygote and affected shows vertical transmission
Remember ideal autosomal recessive is horizontal transmission and can skip a generation
H-antigen is an essential precursor to ABO, and is encoded a fucosyltransferase.
The H antigen is produced by a specific fucosyltransferase. Depending upon a person’s ABO blood type, the H antigen is converted into either the A antigen, B antigen, or both.
H antigen is a precursor to each of the ABO blood group antigens, apparently present in all people except those with the Bombay Blood phenotype (hh).
HH- functional
Hh- functional
hh- non-functional
Bombay blood group: The peculiarity is that they do not express the H antigen. As a result they cannot form A antigens or B antigens on their red blood cells. Thus they can donate blood to anybody with ABO grouping but can receive blood only from Bombay blood group people.e
hh IAIA will have O phenotype
Hh IAIB will have AB phenotype
HH I I will have O phenotype
HH I IB will have B phenotype
