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
What are the rules for sex-influenced trait?
Assume that the trait is dominant in males
but recessive in females.
Assume all outsiders are homozygotes.
Thus:
DD is always affected
dd is always normal
Dd is affected in males, but normal in females
androgenetic alopecia (Pattern Baldness) -Pattern baldness-behaves as autosomal dominant in males and autosomal recessive in females. Expression of the character is influenced by the presence of testosterone.
Males – Aut. Rec inheritance of mutant
Androgen receptor gene (AR gene)
Females – thinning all over scalp, (PCOS, thyroid goiter, neoplasm, menopause)
What are the rules for sex-limited trait?
Assume the trait is dominant but only
expressed in males.
Affected outsider males are heterozygous; unaffected males are homozygous normal
Assume that outsider females are homozygous normal.
breast cancer in men
What is the % of offspring affected for autosomal dominant disorder if 1 heterozygote parent is crossed with an unaffected parent?
50%
What is the % of offspring affected for autosomal recessive disorder if 1 heterozygote parent is crossed with an unaffected parent?
0%
What is the % of offspring affected for autosomal recessive disorder if both parents are heterozygote?
25%
What is the % of offspring affected for autosomal dominant disorder if both parents are heterozygote?
75%
What is the % of offspring affected for X-linked recessive disorder if dad is affected? What about % of affected sons?
0%
males are mostly affected
females could be affected because of lyonization
0%
sons inherit allele from only mother
daughters inherit allele from either parent
What is the % of offspring affected for X-linked recessive disorder if mom is carrier? What about % of affected sons?
25%
50%
What is the % of offspring affected for mitochondrial disorder if mom is affected?
100%
sons and daughters inherit allele only from mom
What is the % of offspring affected for mitochondrial disorder if dad is affected?
0%
sons and daughters inherit allele only from mom
What is Locus heterogeneity (and an example)
Allelic heterogeneity, and Complementation?
Locus heterogeneity – same clinical phenotype caused by different types of mutations in genes at different chromosomal loci
- CFH gene, 1q31.3 – encodes instructions for complement factor H
- ARMS2 and HTRA1 located on 10q26
- Genetic Association: high-density lipoprotein (HDL), human hepatic lipase (LIPC) and cholesterol ester transfer protein (CETP).
Allelic heterogeneity – same clinical phenotype caused by different mutations within the same gene loci
Complementation – mutations producing null alleles in different genes can be compensated in effect (complemented) by another gene’s product.
e.g. profound congenital hearing loss, blindness, some forms of MR, FANC group
What is the difference between dry and wet AMD?
Dry (atrophic) type non-neovascular and non-exudative - -85% to 90% AMD presence of drusen, yellow deposits,
appear on the retina.
wet (exudative) choroidal neovascularization or CNV
- 10-15% growth of abnormal blood vessels from the choroid (choroidal neovascularization
- Abnormal levels of VEGF bleeding of blood vessels and leak fluids (lipids) into the retina forming scar tissue.
Duchenne Muscular Dystrophy expresses what kinds of genetic phenomenons?
DMD - most disabling phenotype
Males have progressive myopathy muscle degeneration
presenting by age 3-5 (slow running, difficulty standing fr/ sitting)
Gower’s maneuver and pseudo hypertrophy of calves 9-12 y.o. immobilized to wheelchair.
BMD – milder Phenotype
Later onset, slower progression (wheelchair immobilized 16yo)
Dilated cardiomyopathy in later life, muscle pain
Activity-induced cramping
Flexion contractures of the elbows
Preservation of neck flexor muscle strength
High frequency new mutation, Allelic heterogeneity,
Carrier manifestation, Variable expressivity
DMD gene encodes dystrophin, X-linked (Xp21)
recessive inheritance
Dystrophin ~ 5% cytoplasmic membrane-associated cytoskeletal protein (largest protein)
Incidence (character) Phenotype Protein amt
DMD 28/100,000 severe <3%
absent
BMD 5/100,000 mild 20-80%
reduced
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 Phenylketonuria Oculocutaneous albinism Alkaptonuria/Ochronosis Gangliosidosis/Sphingolipidosis – Tay- Sachs disease Sulfatidoses – Gaucher disease, Niemann- Pick disease types A and B, Fabry disease Mucopolysaccharidoses – Hurler, Hunter, Morquio Glycogen storage disorders/Glycogenoses – von Gierke, Pompe, McArdle These are all examples of what type of inheritance?
autosomal recessive
Sickle cell anemia occurs because of Glu6 to Val6 mutation.
Healthy child has 97.5% HbA, 0% HbS.
Child with severe SCD has 2% HbA, 95% HbS.
Both have 2% HbA2.
- carrier frequency: 1/10 (African-Americans)
- SCT occurs among about 1 /12 Blacks or African Americans
How does sickle cell disease display heterozygous advantage?
heterozygotes selective advantage:
- All genotypes get infected with Plasmodium falciparum parasite
- Sickling also interferes directly with the parasite’s life cycle within the RBC.
- Genetic Fitness - contribution of genes to next generation, adaptive value = selective value
Fitness value= 1 means full fitness
Estimated fitness values W for the three genotypes in malaria dense environment:
WHbA/HbA = 0.88; WHbA/HbS = 1.0; WHbS/HbS = 0.14
Alpha-thalassemia (α-thalassemia) comes in two clinically significant forms which are?
α gene is not expressed so beta genes are
- Hb Bart syndrome (hemoglobin Bart hydrops fetalis)
- -/–: lethal - HbH (hemoglobin H disease)
- -/-a : severe disease
aa/– (trait)
-a/-a (trait/ carrier)
aa/-a (silent)
aa/aa (Normal)
SC can have pleiotropic effects.
as a vascular disorder:
acute lung syndrome, heart disease, cardiomyopathy, bone deformities, kidney failure, increased susceptibility
to bacterial infections, pain crisis, fatigue, delayed growth and development.
All common signs/symptoms of SC disease.
Example of an Autosomal Recessive Disorder. Cystic Fibrosis (CF).
- CF is an autosomal recessive genetic disorder caused by 1,000 mutations (almost all are point mutations or small deletions 1-84 bp) in the CFTR gene on chromosome 7q31.2 for the cystic fibrosis transmembrane conductance regulator which functions as a chloride ion (Cl) channel. The Cl ion channel normally transports Cl out of the cell and H2O follows by osmosis. The H2O maintains the mucus in a wet and less viscous form.
- CF is most commonly (70% of cases in the North American population) caused by a three base deletion which codes for the amino acid phenylalanine at position 508 (delta F508) such that phenylalanine is missing from CFTR. However, there are a large number of deletions, which can cause CF, and parents of an affected child can carry different deletions of CFTR gene. These mutations result in absent/near absent CFTR synthesis, a block in CFTR regulation, or a destruction of Cl transport.
- The poly T tract/TG tract is associated with CFTR-related disorders. The poly T tract is a string of thymidine bases located in intron 8 with the 5T, 7T, and 9T the most common variants. The TG tract is a repeat of thymidine and guanine bases just 5’ of the poly T tract with repeats that commonly number 11, 12, or 13.
- Sweat chloride test. The pilocarpine iontophoresis for sweat chloride is the primary diagnostic test for CF. [Cl] 60 Eq/L on two separate occasions is diagnostic.
- Prevalence. The prevalence of CF is 1/3,200 in the Caucasian population with a heterozygote carrier frequency of 1/20. CF is less common in the African American population (1/15,000) and in the Asian American population (1/31,000).
- Clinical features include: production of abnormally thick mucus by epithelial cells lining the respiratory resulting in obstruction of pulmonary airways, recurrent respiratory bacterial infections, and end-stage lung disorder; pancreatic insufficiency with malabsorption; acute salt depletion, chronic metabolic alkalosis; and males are almost always sterile due to the obstruction or absence of the vas deferens.
Classic cystic fibrosis is characterized by:
chronic bacterial infection of the airways and sinuses
fat maldigestion due to pancreatic exocrine insufficiency
infertility in males due to obstructive azoospermia,
elevated concentrations of chloride in sweat.
Patients with nonclassic cystic fibrosis
- less severe, have at least one copy of a mutant gene, patients usually have no overt signs of maldigestion.
Variable expression of mitochondrial diseases can be accounted by what phenomenon?
heteroplasmy
LHON
what is the cause of aging? heteroplasmy
Hypophoshpatemic rickets is what inheritance?
X-linked dominant
giving vitamin supplementation will not help because individuals are resistant to it
this is distinguishable from regular vitamin D rickets
What autosomal recessive first inborn error of metabolism discovered gene coding? It is due to the absence of homogentisic oxidase mapped to 3q21. Many different mutations, most often missense. Lack of the homogentisic oxidase leads to the blockage of metabolism of phenylalanine-tyrosine and thus there is increased homogentisic acid depoisits in body. Ochronosis is a connective tissue manifestation of this disorder.
Alkaptonuria - The cartilage is pigmented and destroyed.
most common clinical feature of ochronosis (cartilage is pigmented and destroyed) - ochronotic arthritis
pigment deposition can be seen in skin, bones, articular cartilages, synovial membranes, lungs, heart endocardium and valves, and kidneys
Darkening of urine with exposure to air or reducing agents
This autosomal recessive disease is 1/10,000 Chromosome 12q24.1, > 400 mutations at PAH locus.
Biochemistry: dysfunction phenylalanine hydroxylase –
excessive phenylalanine metabolized to phenylacetic acid
phenylpyruvic, and phenyllactic acid
Null allele - 1200umol/L = classical PKU
Reduced - 600 - 1200umol/L = mild PKU
Reduced – 180 – 600umol/L = mild hyperphenylalaninemia
Phenylketonuria (PKU) Clinical:
-Mental Retardation (MR)
-Neurological abnormalities
-New born screening has improved cognitive development and
eliminated MR
-Begin dietary treatment within first 3 weeks to for best developmental scores continue for 10 years.
Affected infants normal at birth
1st couple weeks, impaired brain development, microcephaly
By 6 months, severe mental retardation – <4% of untreated IQ >50 or 60 – 33% never walk, 66% never talk
What sequence is inserted in exon 11 for Tay-Sachs disease in both Asheknazi and non-Ashkenazi Jews? What mode of inheritance is it?
TATC autosomal recessive chr 15q (hexosaminidase A) loss of function
complete lack of hexosaminidase A activity
–>complete loss of activity = infantile form
G269S mutation –> partially inhibit activity of
hexosaminidase A = adult onset form
Ethnic prevalence Ashkenazi Jewish = 93% exon 11 insertion (1278+TATC) = 75% intron 12 (+1IVS12G-C) = 15% G269S = 3%
non-Ashkenazi Jewish = 25% exon 11 insertion (1278+TATC) = 20% intron 12 (+1IVS12G-C) = 0% G269S = 5%
What are some symptoms of Tay-Sachs disease?
- Flaccid muscles
- exaggerated startle response
- loss of ability to hold up head or sit
- macular cherry-red spot
- Blindness
- Inability to swallow
- Muscular atrophy and paralysis
NOT TREATABLE!!
This autosomal recessive disorder is characterized by GAA repeats.
It exhibits incomplete and complete penetrance.
Normal: 5-33 GAA repeats
Abnormal: 66-1700 GAA repeats (600-1200 common)
Fewer than 5% of the patients are heterozygous for point mutations.
Friedreich Ataxia (FRDA)
GAA repeats –> transcription silencing and reduced expression of frataxin = mitochondrial protein.
–> dysregulation of mitochondrial function, decreased oxidative phosphorylation, increased ROS production –> subsequent mitochondrial and nuclear DNA damage.
late-onset Friedreich ataxia (LOFA) = onset <25y.o..
very late-onset Friedreich ataxia (VLOFA) = onset < 40 y.o.
Huntington disease Thrombophilia Familial Adenomatosis polyposis (FAP) Hereditary Non-polyposis colorectal cancer (HNPCC) Marfan Syndrome Neurofibromatosis I Achondroplasia Retinoblastoma
These are all examples of what mode of inheritance?
autosomal dominant
What are the autosomal dominant inherited disorders with the triplet repeats below?
CGG
CAG
GAA
CTG
Fragile X syndrome
(X-linked)
Huntington’s Disease
Friedreich Ataxia
Myotonic Dystrophy
What the special features of autosomal dominant inheritance
with triplet repeat amplification disorders ?
- Anticipation - increase in severity and age of onset of phenotype in successive generations
- Increased number of affected
- Incomplete penetrance
- Variable expressivity
For example in Huntington's disease:
CAG repeats
Normal 10-20
Premutation 27-41
Affected 36-121
Incomplete penetrance vs complete penetrance
How many repeats is considered premutation and affected in fragile X syndrome, Friedreich ataxia, and myotonic dystrophy?
CGG repeats
Nornal 6-52
Premutation 60-200
Affected 230-1000
GAA repeats Normal 6-34 Premutation 80 Affected 112-1700
CTG repeats Normal 5-34 Affected 50-300
Autosomal dominant HTT (HD) gene, chr. 4p16.3
3 to 7 per 100,000 people of European ancestry.
less common in individuals of Japanese, Chinese, and African descent.
Normal allele. p.Gln18, >36 or more CAG repeats. HD-causing alleles are further classified as:
Intermediate allele: incomplete-penetrance HD-causing alleles - 36-39
CAG repeats = at risk for HD
HD-allele: Full-penetrance HD-causing alleles. p.Gln18 - > 40 CAG repeats development of HD.
Huntington’s Disease
gain of function
Test Method is targeted mutation analysis of CAG trinucleotide repeats which is detected 100% of the time
Clinical signs and symptoms:
- chorea
- mental disturbances including cognitive decline
- changes in personality and/or depression
- abnormal body postures
Genotype-phenotype correlation
- adult onset form= 40-50 CAG repeats
- juvenile onset form= >60 CAG repeats
mean age of onset is 35 to 44 years and the median survival time is 15 to 18 years after onset.
This autosomal co-dominant disorder involves mutations in the SERPINA1 gene that lead to quantitative deficiency or abnormal form of AAT. AAT is a proteinase inhibitor which blocks/destroys elastase thus protects the body from self destruction by neutrophil elastase.
alpha-1 antitrypsin (AAT) deficiency
M allele (most common) = produces normal levels AAT
S allele produces moderately low levels AAT
Z allele produces very little= AAT = Glu ∆ Lys 342 (exon 5)
MM = Normal SS = At risk SZ = At risk ZZ = AAT deficiency
Remember it is CODOMINANT INHERITANCE
What are some symptoms of alpha-1 antitrypsin?
hepatocyte inclusions
hyaline globules
emphysema - develops ages 20 and 50
recurring respiratory infections, shortness of breath, fatigue, and rapid heartbeat upon standing.
10 % of infants develop liver disease –> jaundice
15 % of adults develop liver cirrhosis
at risk for hepatocellular carcinoma
Environmental factors, tobacco smoke, chemicals, and dust, impact severity
This autosomal dominant syndrome has a mutation in FBN1 gene, chr 15q21.1.
FBN1 gene encodes fibrillin-1, a glycoprotein that is the main constituent of the microfibrils of the extracellular matrix.
Inheritance features: variable expressivity (severity), age of onset, and rate of progression
Incidence 1 in 5,000 to 1 in 10,000 live newborns worldwide
25% de novo mutations
missense mutations in exons 24–32 tend to predict more a severe phenotype.
Marfan’s Syndrome
Reduced or abnormal fibrillin-1 leads to tissue weakness, increased transforming growth factor ß signaling, loss of cell–matrix interactions
Microfibrills found in ECM, cell rigidity, flexibility, and physiology
disorder that affects the connective tissue
Skeletal
disproportionately long bones (e.g. arachnodactyly).
Protruding or indented sternum = pectus caranatum or pectus excavatum
Scoliosis - side to side curvature
Lordosis - inner curvature of lower back
Kyphosis – outward curvature on the spine of upper back
Eyes Dislocation of lenses Nearsightedness Retinal Detachment
common Retinal
Early development of Glaucoma or cataracts
Heart and blood vessels
Abnormally large mitral valve mitral prolapse and regurgitation (75% of
cases)
Heart murmurs
These are clinical presentations of what syndrome?
Marfan’s syndrome
This autosomal dominant disorder of bone growth is a result of mutation in the FGFR3 (fibroblast growth factor 3).
(p.Gly380Arg ), chr 4p16.3
1 /15,000 -1/40,000 live births
intelligence and life span is usually normal
FGFR3 gene encodes fibroblast growth factor receptor 3 –>
functions to converting cartilage to bone
What is this condition and how is the majority of its cases inherited?
Achondroplasia
80% of affected are non-inherited, but de novo mutations
Inherited: 50% chance of children born to 1 affected parent, 25% chance for normal offspring of 2 affected parents
What are some phenotypic differences between achondroplasia and hypochondroplasia?
Achondroplasia
Adult male - avg. height = 131 cm(4 ‘ 4”), and the
Adult females – avg. height = 124 cm (4’ 1”)
average-size trunk
short arms and legs
limited range of motion at the elbows
macrocephaly with a prominent forehead.
Hypochondroplasia
Milder form of achondroplasia
Adult height - 165 cm (5’ 4”)
This is an autosomal dominant disease also known as Von Recklinghausen disease. It is a result of mutations in NF1 (17q11.2). NF1 is a tumor suppressor, controlling cell growth thus this disease results in a loss-of- function.
Neurofibromatosis I
NF1 encodes for neurofibromin
neurons, oligodendrocytes and Schwann cells expression
–> form myelin sheaths
Clinical presentations:
café-au-lait spots, neurofibromas, optic
gliomas, plexiform neuromas,
G6PD, Hemophilia A, Alport syndrome, Vitamin D- rickets, OFD syndrome are examples of what sex related inheritance?
X-linked Recessive – Ex. G6PD, Hemophilia A, Alport syndrome
X-linked Dominant – Ex. Vitamin D- rickets, OFD syndrome
Oral-facial-digital syndrome (OFD)
Which sex-linked inheritance has these characteristics?
- Mothers pass their X’s to both sons and daughters
- Fathers pass their X to daughters only.
Normal outsider rule for dominant pedigrees for females, but for sex-linked traits remember that males are hemizygous and express whichever gene is on their X.
X-linked dominant
Females Transmit with Affect
Affects ½ of offspring of both sexes
Variable expressivity wide in females-less so in males
Non-penetrance (skipped generations) may occur in females but not with males
What are the Mendelian inheritances related to sex differences?
X-linked recessive X-linked dominant Y-linked or holandric Autosomal sex influenced Autosomal sex limited
affected are male (hemizygous)
Female carriers (non to mild condition)
Mothers of affected children have affected brothers
No father-to-son transmission
All daughters of affected males carry abnormal gene
These describe what mendelian inheritance?
X-linked recessive
What are the features of X-linked dominance?
- Uncommon and infrequent
- Vertical transmission
- Female frequency of affected much higher than males
- No male-to-male transmission
- All daughters of affected male affected
- Affects ½ of offspring of both sexes
- Variable expressivity wide in females-less so in males
- Non-penetrance (skipped generations) may occur in females but not with males
- Vitamin D resistant rickets and Alport Syndrome
Only Males Affected Females Transmit without Affect No male-to-male transmission Affects ½ of male offspring of Carriers May be structural genes (e.g. DMD) enzymes (ADA deficiency, OTC) Receptors (SCID)
What is this mode of inheritance?
X-linked recessive
Traits on the Y chromosome are only found in males, very rarely in females.
The father’s traits are passed to all sons.
Male-Male Transmission
There is only 1 copy of each Y-linked gene (hemizygous).
Near 100% Penetrance
Nearly all genes function in testicular, sperm maturation.
What is the mode of inheritance?
Y-linked Inheritance
Hemophilia A - clotting disorder, deficiency of factor VIIIa
Hunter’s syndrome - metabolic storage deficiency of mucopolysaccharides
Lesch-Nyhan Syndrome - metabolic abnormality with mental retardation, self-destructive behavior & hyperuricemia
Glucose-6-Phosphate Dehydrogenase (G-6-PD) deficiency - hemolytic anemia produced by exposure to a variety of drugs, e.g., antimalarials
Duchenne Muscular Dystrophy - a degenerative muscular disease that starts in early childhood
Red-greed color blindness - inability to distinguish red or green colors
These are all examples of what mode of inheritance?
X-linked recessive
Which deficiency is X-linked recessive and is hemolytic anemia produced by exposure to a variety of drugs, e.g., antimalarials?
This disorder is most frequently seen in malaria dense areas.
most common enzyme deficiency worldwide
spectrum of disease including neonatal hyperbilirubinemia, acute hemolysis, and chronic hemolysis
displays heterozygote advantage
Glucose-6-Phosphate Dehydrogenase (G-6-PD) deficiency
G6PD catalyzes the first step in the pentose phosphate pathway converts glucose to ribose-5-phosphatein.
Overall reduced production of NADPH due to deficiency
NADPH is needed for glutathione reduction, red blood cells are unable to protect themselves from the damaging effects of ROS.
What is germline mosaicism?
In autosomal dominant disorders, new mutations are relatively common. In these cases, there will be an affected child with no family history of the disorder. There is a low recurrence risk (1%–2%) due to the possibility of germ line mosaicism. Germ line mosaicism is the presence of more than one cell line in the gametes in an otherwise normal parent and is the result of a mutation during the embryonic development of that parent. There is an increased risk for a new dominant mutation in fathers over 50 years of age.
What is mosaicism in females?
X chromosome inactivation makes females functionally hemizygous. X chromosome inactivation begins early in embryological development at about the late blastula stage. Whether the XM or the XP becomes inactivated is a random and irreversible event. However, once a progenitor cell inactivates the XM, for example, all the daughter cells within that cell lineage will also inactivate the XM (the same is true for the XP ). This is called clonal selection and means that all females are mosaics comprising mixtures of cells in which either the XM or XP is inactivated.
What symptoms should you see in neonates to consider G6PD deficiency?
neonates who develop hyperbilirubinemia within
the first 24 hours of life
a history of jaundice in a sibling
bilirubin levels greater than the 95th percentile
children with a family history of jaundice, anemia, splenomegaly, or cholelithiasis
Male of Asian, Mediterranean or African ancestry
What is the role of vitamin E, favism and plasmodium?
individuals with G6PD mutation and favism in diet show the G6PD phenotype (block GSH and ability to produce water from H202)
Vitamin E: reduce the amount of methemoglobin, Heinz body formation, RBC membrane damage
Plasmodium parasites cannot adapt to the high H2O2 environment
What is the mechanism of action in G6PD deficiency?
SIRT2 (deacytylation) and KAT9/ELP3 regulate G6PD activation via K403 acetylation.
K403 acetylation decreases G6PD activity by inhibiting dimer formation.
What is the mechanism of action in G6PD deficiency?
SIRT2 (deacytylation) and KAT9/ELP3 regulate G6PD activation via K403 acetylation.
K403 acetylation decreases G6PD activity by inhibiting dimer formation.
Regulation of G6PD K403 acetylation modulates NADPH homeostasis and cell survival during oxidative stress.
What are Heinz body in relation to G6PD?
GSH protects the hemoglobin from oxidative denaturation to Heinz bodies.
Heinz bodies composed of denatured hemoglobin, attach to the RBC membrane, and this leads to increased membrane permeability and rigidity and removal by the spleen.
There is a loss of function in hemophilia A where the activity of Factor VIII is usually no greater than 1%. What type of mutation occurs for this disease and what is its inheritance?
X-linked recessive qter
ter=terminal
43% of severe and 25% of all FVIII patients carry an inversion at tip of Xq
Occurs in male meiosis
Symptoms usually develop in severe cases – disease with serious bleeding, hemoarthrosis, bruising, hemorrhage after trauma or surgery
What is the X-linked recessive syndrome in which patients have to be restrained with or they will claw themselves?
Lesch-Nyhan Syndrome
shows variable expressivity
Sex linked mutations in the HPRT1 gene
Overproduction hyperuricemia
nonfunctional HGPRT, ↑ in PRPP, causes ↑ AMP & GMP (RNA), leads to
↑unused and degraded uric acid products
What are examples of X-linked dominant disorders?
X-linked hypophosatemic rickets (Vitamin D resistant rickets)
-can be more severe in males than female
Rett syndrome- lethal in males prenatally; Mutation in MECP2 gene on X-chromosome
