Unit II Flashcards
What is important about meiotic prophase I?
Reciprocal recombination occurs here
What are bivalents?
Maternal and paternal homologs of
each chromosome become paired or synapsed along their entire lengths, forming
structures known as “bivalents”.
What is the synaptonemal complex?
a proteinaceous structure which promotes inter-homolog interactions.
Define chiasmata
attachments or crossovers
Which step of meiosis is most error prone?
Meiosis I during chromosome nondisjunction
What is the proband?
The affected individual through whom a family with a genetic disorder is ascertained
What is the consultand?
The individual (not necessarily affected) who presents for genetic evaluation and through whom a family with an inherited disorder comes to attention.
Define consanguinity
identifies cases of genetic relatedness between individuals descended from at least one common ancestor.
Define Phenotype
The observable expression (of a genotype) as a morphological, clinical, cellular, or biochemical trait
Define Genotype
The set of alleles that make up his or her genetic constitution
Mendelian Inheritance
disorders that are due to the predominant effects of a single mutant gene
Mendel’s First Law
The Law of Segregation
What is the law of segregation?
At meiosis, alleles separate from each other such that each gamete receives one copy from each allele pair
What is Mendel’s Second Law?
That Law of Independent Assortment
What is the Law of Independent Assortment?
At meiosis, the segregation of each PAIR of alleles is independent.
Define Codominant
If both traits (alleles) are expressed in the heterozygous state
Define Semi- Dominant or incomplete dominant
The heterozygous phenotype is intermediate between the two phenotype. A degree of both phenotypes combined.
Define hemizygous?
A chromosome in a diploid organism is hemizygous when only one copy is present.
Define Expressivity
The degree to which a trait is expressed in an individual (is a measure of
severity). Expressivity is analogous to a light dimmer (the light is ‘on’ but the brightness
(expressivity) exists along a spectrum (of severity)). The variation in phenotype is
explained (in part) by sex influence, environmental factors, stochastic effects, and
modifier genes.
Sex Influence
Phenotypic expression in some conditions is
dependent on the individual’s sex (e.g. gout is more common in males than
premenopausal females)
Sex limitation
occurs if only one sex can express a phenotype
e.g. unicornuate uterus
Environmental factors
Some environmental factors can affect the expression of
Mendelian diseases. The disease may only manifest in individuals if particular
environmental factors are present.
Example: In acute intermittent porphyria, episodes of
abdominal pain and psychiatric illness are dependent on exposures (alcohol,
medications).
Stochastic Effects
Stochastic (random) effects can influence the expression of
phenotypes. This concept pays homage to the fact that some phenotypes may be
influenced by chance events/processes absent any obvious genetic/environmental factor.
Modifier genes
Genetic factors outside of the genetic locus causing a disease can be
important for the expression of Mendelian diseases.
Phenocopies
Diseases (traits) that are due to non-genetic factors.
Example: A thyroid
cancer due to radiation exposure cannot always be distinguished from a thyroid cancer
due to mutations in RET gene.
Pleiotropy
Used to describe multiple different phenotypic effects due to mutation(s) in a
single gene. Often used, when the phenotypes are seemingly unrelated and/or in
multiple different tissues.
Example: Neurofibromatosis Type I leads to: café au lait spots
(skin), neurofibromas (peripheral nervous tissue), hammartomas in the eyes (ocular),
abnormal freckling (skin again), and learning difficulties (central nervous system).
Penetrance
The fraction of individuals with a trait (disease) genotype who show
manifestations of the disease.
Penetrance is analogous to a light switch (can be ‘on’ or ‘off’).
How frequently is a SNP likely to occur between two individuals?
1 in every 1000 bp
Name a chromosome that is gene rich?
Chromosome 19
Name a chromosome that is gene poor?
Chromosome 13, 18, 21
Is most of the genome stable or unstable?
stable
Percentage of genome that is GC rich?
38%
Percentage of genome that is AT rich?
54%
What percent of genome is protein coding?
1.5%
What percent of the genome is represented by genes?
20-25%
percent of genome that is repeptitive dna?
40-50%
alpha satellite repeats
171 bp repeat unit near the centromere.
may be important to chromosome segregation in mitosis and meiosis.
Alu family
example of DISPERSED DNA repeats about 300 bp in length.
500,000 copies in the genome
retrotransposition can cause insertional inactivation of genes via non-allelic homologous recombination
L1 family
An example of DISPERSED DNA repeats about 6 kb in length
100,000 copies in the genome
can lead to disease via non-allelic homologous recombination
Microsatellites
2-4 bp nucleotide repeats
5x10^4 per genome
aka short tandem repeat polymorphism
Useful in DNA fingerprinting
Minisatellites
tandem repeats about 10-100 bp
aka variable nucleotide tandem repeats.
useful in DNA fingerprinting
Gene Families
Gene family is composed of genes with high sequence similarity (e.g. >85-90%) that may carry out similar but distinct functions
Copy number variation
primary type of structural variation
may cover 12% of genome
involved in rapid & recent evolutionary changes
Link between evolutionary adaptive copy number increasing and increase in human disease. EX: 1q21
When does the synaptonemal complex disassemble?
At the end of prophase I
Define metacentric
the centromere is located in the middle of the chromosome,
such that the two chromosome arms are approximately equal in length.
Submetacentric
the centromere is slightly removed from the center
Acrocentric
the centromere is near one end of the chromosome
heterochromatic regions are right with what nucleotides?
AT
Euchromatin is __ rich?
GC
G banding uses what type of dye?
Giemsa
G banding stains what structures?
heterochromatic/ AT regions which are typically gene poor
Aneuploidy
the condition in which cells contain an abnormal chromosome number
Monosomy
the condition in which a cell lacks one copy of a chromosome
trisomy
the situation in which an extra copy of an entire chromosome is
present in the cell.
Most common cause of down syndrome?
nondisjunction during maternal meiosis I
Tolerated Aneuploidy conceptions?
45 X, trisomy 16, 21, and 22
Tolerated Live Birth Aneuploidy
Trisomy 13, 18 or 21
Gain of X and Y chromosome
Loss of X or Y chromosome
List the characteristics of Down Syndrom
Trisomy 21
Short stature Hypotonia Moderate intellectual disability Cardiac anomalies / congenital heart defect leukemia in infancy early onset Alzheimers hearing loss
Trisomy 18
Edwards syndrom small for gestational age small head clenched fingers rocker bottom feet
Most common chromosomal abnormality in spontaneous abortions?
Turner Syndrome (loss of X chromosome)
Phenotype of Turner Syndrome
(loss of x chromosome)
short stature webbed neck edema of hands and feet broad shield like neck gonadal dysgenesis renal and cardiovascular anomalies
Klienfelter syndrome
male with extra X chromsome
XXY
Mosaicism
Mosaicism is defined as the presence of at least two genetically different cells in a
tissue that is derived from a single zygote.
EX: mosaicism turner syndrome has a chromosomal change in only SOME of their cells. Some cells have 46 chromosomes and others have 45
Trisomy 13
Patau Syndrome Most clinically severe of the 3 CNS abnormalities Omphalocele (herniation of GI organs outside abdomen) Renal dysplasia Congenital heart disease
Describe a paracentric inversions
inversion that occurs outside of the centromere. During meiosis, an inversion loop is required for the associated regions to align. If a crossover occurs WITHIN the loop, you end up with a chromosome that has two centromeres (dicentric) and one WITHOUT a centromere (acentric)
= infertility
Describe a pericentric inversion
inversion that occurs within the centromere. During meiosis, an inversion loop is required for the associated regions to align. If cross over occurs WITHIN the loop, you end up with a chromosome that is unbalanced with both having some duplications and some deletions.
What is a Reciprocal Translocation?
results from the breakage and rejoining of non-homologous
chromosomes, with a reciprocal exchange of the broken segments.
creates quadrivalent so all four chromosomes can align
What is a Robertsonian Translocation?
the fusion of two acrocentric chromosomes within their
centromeric regions, resulting in the loss of both short arms (containing rDNA repeats).
What type of rearrangement is a Robertsonian translocation?
A BALANCED ONE.
It does result in a reduction of chromosome however the loss of ribosomal DNA is not considered deleterious
What is the outcome of a Robertsonian translocation
The carrier is phenotypically normal however the rearrangement may lead to unbalanced karyotypes in their offspring. Can lead to monosomies or trisomies in their offspring
What is an unbalanced rearrangment?
The chromosome set has additional or missing material
What are some of the outcomes of unbalanced rearrangement?
Duplication of genetic material can lead to partial trisomies.
Deletions of genetic material can lead to monosomies.
Phenotypically ABNORMAL
What are the two most common chromosomes involved in Robertsonian translocation?
Chromosomes 13 and 14.
Can occur in chromosome 21
Which chromosomes are acrocentric?
13, 14, 15, 21, and 22
Which acrocentric chromosomes are most commonly fused together?
13 and 14
14 and 21
What are the benign pericentric inversions?
9 qh, 16 qh, 1 qh, and Yqh
These are within the heterochromatic region
Does NOT result in spontaneous abortions, infertility, or recombinant offspring
What is the risk of a balanced translocation carrier having an unbalanced progeny?
0-30%
maternal carriers are morel likely to have a progeny with a phenotype
Incidence of Inversion structural rearrangements?
1%
What percentage of meiotic recombinations for inversion carriers lead to a normal progeny or balanced progeny?
50%
Numerical abnormalities vs. structural abnormalities?
Numerical abnormalities are more common than structural abnormalities
Define Epigenetic
Mitotically and meiotically heritable variations in gene expression that are not caused by changes in DNA sequence
EX: post-translational modifications of histones and DNA methylation.
Name a couple of proteins that recognize methylated DNA and play a role in gene silencing
HDAC
MeCP2
Where does methylation of DNA take place?
CpG islands
What is the function of DNA methylation?
Usually gene silencer BUT in some cases acts as a gene activator!
What is genetic imprinting?
Sex-Dependent epigenetic modulation of regulatory regions such as promoter sequences
What percent of the human genome is imprinted?
Less than 10%
What enzyme is responsible for the propagation of methylated marks?
Maintenance methyltransferase
Describe Epigenetic Reprogramming
In primordial germ cells demethylation occurs. If you produce oocytes, the specific corresponding region is methylated. If you produce sperm, then the male corresponding region is methylated.
Somehow the cell KNOWS. So that you pass on the correct methylation pattern to your progeny.
What causes Prader Willi Syndrome?
Deletion of paternal 15q 11- 13
What percentage of Prader Willi Syndrome is due to deletion of paternal chromsome 15?
70%
What percentage of PWS is caused by maternal uniparental disomy?
28%
Percent of PWS caused by imprinting centre mutation on paternal allele?
What is the major cause of Angelman Syndrome?
Deletion of maternal chromosome 15 q 11- 13
What percent of Angel Syndrome is caused by deletion of maternal chromosome 15?
70%
What percent of AS is caused by paternal uniparental disomy?
4%
What percent of AS is caused by imprinting center mutation on maternal allele?
8%
What percet of AS is caused by mutation of UBE3A on maternal allele?
8%
Which cells undergo universal demethylations?
Primordial cells
What is the outcome of maternal uniparental disomy of chromosome 15?
Prader Willi Syndrome
What is the outcome of paternal uniparental disomy of chromsome 15?
Angelman syndrome
What leads to the deletion of PWS And AS genes?
misalignment and homologous recombination
Significance of gene HERC2
generates repeats that flank the 15q 11 -13 region on chromosome 15
Prader-Willi Syndromes
short stature
excessive eating
hypogonadism
some degree of intellectual disability
Angelman Syndrome
Severe intellectual disability
Spasticity
Seizures
Short stature
Cancer Cytogenetics is important for what two diseases?
Leukemia and lymphomas
What test is used for the diagnosis of children with developmental delays?
Chromosomal Microarray (CMA) AKA Array CGH
What two tests do you use to investigate leukemia and lymphoma?
Chromosome analysis and FISH
Name the specimens used in cancer diagnostics
Bone Marrow Unstimulated Blood Lymph node tissue Solid tumor tissue Cerebrospinal fluid
What are the uses of FISH?
INITIAL differential diagnosis
monitor treatments or disease progression
Auer Rod
Suggests Myelogenous Leukemia
What are some of the key differences of MicroArray vs. regular Cytogenetics techniques?
Chromosomal Microarray detects gains and losses ONLY
It uses interphase DNA instead of mitotic cells
Analyzes ALL CELLS
Technology Dependent
Detects runs of homozygosity
What is the threshold for CMA detecting runs of homozygosit
can evaluate greater than or equal to 5 Mb with a 10 Mb threshold
Limitation of CMA
Cannot detect very low level mosaicism, heterodisomy, or balanced chromosome rearrangement
Protocol for child with developmental delays
- If deletion or duplication is detected by CMA consult Database of Genomic Variance
- Parental FISH studies will be offered to determine if this finding is a rare,
normal, familial variant. - If a deletion or duplication is found in one or both parents, other family
members may be tested by FISH. Often extensive consultation between
the clinical geneticist, genetic counselors and cytogeneticist are required. - If the deletion or duplication is not found in either parent, and it is not found in
the genomic variants Database, further data-base mining, literature
searches are performed. Often a gene or genes mapped in the region of
deletion or duplication reveals a syndromic association.
Pharmacogenetics
Variable response due to individual genes
Pharmacogenomics
Variable response due to multiple loci across the genome
Pharmacokinetics
the rate at which the body absorbs, transports, metabolizes, or excretes drugs or their metabolites
“What the body does to the drug”
Pharmacodynamics
The differences in the way the body responds to the drug.
“What the drug does to the body”
Phase I drug metabolism
the introduction of a more polar group to a compound that allows a side group to be more readily attached
The hydroxyl group attached in phase I
provides a site for a sugar or acetyl group to be attached to the drug to detoxify it and make it much easier to excrete in what is referred to as phase II of drug metabolism
Mutation that causes cytochrome P450 to have no activity
splicing or frameshift mutations
Mutation that causes REDUCED activity in cytochrome P450
missense mutation
Where are are the gene products of CYP450 most active?
Mostly in the liver.
Also, intestinal epithelium
What are the three main families of the CYP450 gene?
CYP1, CYP2, CYP3
Significance of CYP3A4
takes part in metabolism of 40% of all drugs
Drugs that CYP3A metabolizes
Felodipine (CA channel blocker that can be used for hypertension) and Cyclosporine (immunosuppressant)
CYP3A inhibitors
grapefruit juice and ketoconazole (an antifungal agent)
need to reduce drug dosage so that patient does not suffer from drug toxicity
CYP3A inducers
rifampicin.
Need to increase drug dosage
important difference of CYP2D6 gene?
It ACTIVATES codeine into morphine
Drugs that the NAT gene metabolizes?
Isonizad for tuberculosis
Drug that the TMPT gene metabolizes?
6-mercaptopurine and 6-thioguanine
clinical relevance of the TMPT gene?
6-mercaptopurine is a drug used to treat ALL but in .5% of children the TPMT activity is so low (due to a mutation) that drug toxicity can occur and the child will die. Only 10% of standard drug dose is needed for these children.
TPMT is an enzyme transcribed from the TMPT gene and detoxifies the 6-mercaptopurine drug.
What drugs does the VKORC gene metabolize/
Warfarin which is a blood thinner that is always started at 5 mg/day and then adjusted from there
Define Heritability of a trait
The proportion of total variance in a trait the at is due to variation in genes
Heterogeneity in Cystic Fibrosis
Different alleles at same location can cause CF
Heterogeneity in Alzheimers
Alleles at different location or Loci can cause AD
Example of diesease that demonstrate multifactorial inheritance
Some cancers diabetes I and II Alzheimers Inflammatory bowel disease Asthma Schizophrenia Hypertension Cleft lip / palate Rheumatoid arthritis
Odds ratio
Risk of disease if carrying a given gene variant/ risk of disease if not carrying a given gene variant
How do we find diseases today?
Start with disease –> MAP genome –> find gene –> figure out its functio
Linkage Diequilibrium tends to occur within..
haplotype blocks because they are so close together that recombination does not typically occur
Candidate Gene DNA sequencing
Hypothesis driven
“I think this disease is caused by this gene”
Leads to FALSE POSITIVES 97% of the time
What are the two fatal flaws in Gene-by-Gene Case control design?
Stratification - no such thing as a homozygous population
Publication bias - the only studies that get published are the ones with positive confirming results
Describe what a Genetic Linkage Study is
Using patterns of inheritance to guess whats going on in a rare disorder
When should you use Genetic Linkage Study?
For UNCOMMON Mendelian traits
Define CentiMorgan
unit of genetic distance/recombination
LOD
“Log of Odds”
statistical measure of likelihood that loci are linked together given the inheritance/disease pattern
Level of LOD that confirms loci are linked?
> 3
Name the hypothesis-free approach to finding a disease,
Genetic Linkage
Genome-Wide Association Study
Describe Genome Wide Association Study (GWAS)
Tests ALL parts of the genome simultaneously between individuals for patterns of SNPs associated with diseases
Pros of GWAS
can accurately measure and correct for population stratification
You know the number of tests performed genome-wide (don’t care about other studies)
When is GWAS most useful?
For COMMON alleles with small to moderate effect size
Can discover NEW genes as well
Benefits of Exome/Genome Sequencing
You sequence the coding region oof the genome and can combine result with other affected family members to narrow down the cause of disease.
Will eventually be replaced BY GENOME SEQUENCING
Cons of Exon/Genome Sequencing
Data interpretation can be difficult due to Variant of Unkown Significance.
Creates a lot of “noise”
What are the most commonly used types of DNA polymorphisms for finding genes?
- Microsatellites
- Single-Nucleotide-Polymorphisms (SNPs)
- Copy-Number-Variants (CNVs)
What is allelic heterogeneity?
The existance of multiple mutant alleles of a single gene
Define compound heterozygote?
One who carries two different mutant alleles of the same gene
Phenylketonuria phenotypes
High phenylalanine level in the blood hyperactivity epilepsy mental disability microcephaly
What type of disorder is Phenylketonuria?
Autosomal Recessive
Biochemical cause of Phenylketonuria?
mutation in PAH that encodes phenylalanine hydroxylase (PAH) in 98% of case.
PAH converts phenylalanine to tyrosine
Biochemical cause of Phenylketonuria in 1-2% of cases
Defects in the PAH cofactor BH4 that disrupts production of tyrosine, dopamine, and serotonin
Where is the PAH gene located?
12q22-24
What type of heterozygote are PKU patients?
compound heterozygotes
How to manage PKU in patients?
Low phenylalanine diet.
Phenylalanine is an essential amino acid so you need some
Describe maternal PKU
Not dictated by the child’s gene. Mom who is not on a restricted diet will lead to an increase in F in the maternal circulation leading to MISCARRIAGE and DEVELOPMENTAL ABNORMALITIES
Timing for newborn PKU screening
newborn won’t have elevated F because mom’s enzyme was working. Need to wait a couple days after birth to compare.
How to test of newborn PKU?
Mass spectroscopy
Guthrie test
The old way to test for PKU.
thienalalnin inhibits growth of bacteria. This can be inhibited by high level of phenylalanine causing bacteria to grow = + test
Clinical features of alpha 1-antitrypsin deficiency (ATD)
emphysema (shortness of breath)
increased risk for liver cirrhosis
LATE ONSET
Population most affected by ATD?
Northern Europeans
Biochemical defect in ATD?
Deficiency in protease inhibitor alpha1-antitrypsin (SERPINA1, AAT) which inhibits elastase
Function of elastase
breaks down elastin in CT
Function of Z allele in ATD
Glu342Lys and the Z allele protein is not folded properly and accumulates in liver cells leading to liver damage
ZZ genotype = 15% normal alpha1-antitrypsin function
Function of S alleles in ATD
Glu264Val makes unstable SERPINA1 protein
50-60% of normal SERPINA1 level
What environmental factor aggravates ATD?
smoking
Treatment for ATD
intravenous infusion and aerosol inhalation of SERPINA1
Tay-Sachs Disease Phenotype
progressive destruction of the central nervous system
neurological deterioration 3-6 months
Die by 2-4 years
First signs of Tay-Sachs Disease?
muscle weakness and startle response at sudden sound
Who is at most risk for Tay-Sachs disease?
Ashkenazi Jews
Biochemical defect in Tay-Sachs disease?
Inability to degrade GM2 ganglioside which leads to a build up within lysosomes in neurons found in the CNS
Defective Hexoaminidase A enzyme
What gene causes Tay-Sachs?
HEXA
What mutation causes Sanhoff Disease?
HEXB gene and affects HexA and HexB enzyme activity
AB variant Tay Sachs disease
rare form that does not affect Hex A or Hex B activity. Instead mutation on the GM2 activator protein which leads to build up of GM2 ganglioside
What is Turner’s Syndrome?
Sex chromosome disorder. Women missing an X chromosome 45X
Turner Syndrom CVS abnormalities
aortic coarctation
bicuspid aortic valve
systemic hypertension
conduction difficulties
Turner Syndrome Abnormalities of the eye
inner epicanthal folds
ptosis (drooping of the eye)
Blue Sclera
Turner syndrome abnormalities of Skeletal System
Short 4th metacarpal
short stature
Turner syndrome abnormalities of the Neck
Web neck
low hairline
cystic hygroma
Turner syndrome learning abnormalities
difficulty in math
visual spatial skills
low non-verbal skills
Turner syndrome abnormalities of chest
widely spaced nipples
Trisomy 21
95% of patients with Down Syndrome
due to nondisjunction in maternal meiosis I
Unbalanced Translocation Trisomy 21
3-4% of patients with Down Syndrome
Due to a Robertsonian Translocation leading to the fusion of chromosome 21 and 14
Mosaic Trisomy 21
1-2% of patients with Down syndrome
mixture of normal and abnormal cells
milder symptoms
DS phenotypes
upslanting palpebral fissure epicanthal folds midfacial hypoplasia small ears large appearing tongue low muscle tone
CVS problems with DS
congenital heart disease atrioventricular canal (hole between all four heart chambers)
GI problems with DS
esophageal atresia - leads to blind pouch rather than stomach
What is the significance of polyhydramnios
Child is unable to swallow amniotic fluid
What chromosome defect causes Prader-Willi?
15q11-13
Chorionic villus sampling
a prenatal test that is used to detect birth defects, genetic diseases, and other problems during pregnancy. Sample taken from the placenta where it attaches to the wall of the uterus.
What test is used to test DS?
FISH
What test is used to test for Prader Willi?
FISH or microarray
II. Methylation testing
Physical features Prader Willi?
hypotonia
undescended testes
lighter pigmentation
feeding issues
Toddler Prader Willi features?
Increase appetite
persistant hunger
Eye medical problems with Prader Willi
strabismus - lazy eye
nystagmus - jiggly eye
Developmental abnormalities Prader Willi
mild-moderate developmental delays
behavioral issues
What chromosomal abnormalities are linked to autism?
IDIC 15
Maternally inherited interstitial duplication
What is the Cause of Kleinfelter Disease?
47 XXY
Kleinfelter behavioral childhood presentation
childhood- learning disability
delayed speech and language
tendency to be quiet
Kleinfelter phenotype
tall stature small testes reduced facial hair infertility hypospadia - urethra is underside of penis gynecomastia - enlarged breasts in males
What is the genomic abnormality Jacobs Syndrome
47 XYY
Signs of Jacob’s disease
learning disabilities speech delays developmental delays behavioral and emotional difficulties autism spectrum tall stature
Signs of Triple X syndrome
learning disabilities delayed speech delayed motor seizure kidney abnormalities
5 alpha reductase deficiency
can’t convert testosterone to dihydrotestosterone
under virilized male then increased during puberty
Gene involved in Digeorge Syndrome?
22q11.2
Presentation of Digeorge Syndrome?
Cleft lip / palate
congenital heart disoders
Thymus defect
parathyroid defect
What percentage of babies with Down syndrome also have congenital heart defects?
40-50%
If a pregnant 40-year-old woman presents to your office at 16 weeks of gestation, what standard test are you likely to perform to rule out Down syndrome?
amniocentesis and FISH
What is the Karyotype for Patau syndrome?
Trisomy 13
How are imprinting patterns maintained in offspring?
Maintenance methylation
Prader-Willi and Angelman’s syndromes result from genetic aberrations to the same region of chromosome 15. Which of the following correctly explains why the resulting phenotypes differ from each other?
Phenotype depends on whether the mutation is maternal or paternal in origin.
Their effects are dependent on sex-specific methylation patterns that silence the only good copy of a gene.
essential characteristic for normal epigenetic marking to be successful?
- Modification must be established in gametes
- Must be stably maintained after fertilization
- Must be reversible so appropriate sex-specific imprint is passed on
What is the purpose of a whole chromosome paint using FISH?
identification of markers and translocations
What is the recurrence risk for DS?
1/100 (1%) plus maternal age risk
Single Palmer crease and wide space between 1st and 2nd toe are phenotypes of what disease?
Down Syndrome
Define Pseudogene
They are non-functional genes that can be synthesized through reverse transcription
What is the karyotype for Edward’s syndrome?
Trisomy 18
What are the phenotypes associated with Edward’s syndrome?
small for gestational age microcephaly clenched hands/overlapping fingers Rocker bottom feet Heart/brain abnormalities 90% perinatal lethality
What are the phenotypes associated with Patau syndrome?
Characteristic facies severe intellectual disabilities Congenital malformations (fusion of brain lobes, facial clefts, polydactyly, renal defects)
Describe the alpha cluster in the alpha globin gene
zeta - alpha 2 - alpha 1 on CHROMOSOME 16
Describe the beta cluster
epsilon - gammaG - gammaA - delta - beta on CHROMOSOME 11
HBA
Majority of hemoglobin made up of alpha2 and beta2
Hb Gower I
zeta2 and epsilon2
Hb Gower 2
alpha 2 and epsilon2
Hb Portland
zeta2 gamma 2
Globin Switching part I
turn off zeta and epsilon, turn on alpha and gamma during early embryogenesis
Globin Switching part II
turn off gamma and turn on delta and beta at time of birth
HBF
Fetal Hemoglobin alpha2-gamma2
Has higher affinity for O2 at low pO2 than HbA
Hispanic Thalassemia
Caused by the deletion of the Locus Control Region (LCR) on the beta like cluster
Example of Qualitative Hemoglobinpathies
Hb^Kemsey (binds oxygen too tight)
Hb^Kansas (bind too weak)
HBSS
mutation glutamate –> valine at codon 6
Hemoglobin is now 80% less soluble when not bound to O1 and polymerizes into long fibers
HbCC
Milder form of hemolytic anemia
mutation glutamate –> lysine at codon #6
forms crystals
Sickle Cell trait
HbS trait
heterozygous HbS/HbA
clinically normal except when under severe low pO2
Restriction enzyme used to distinguish sickle cell from wild type?
MstII
cannot distinguish Hemoglobin C disease!
Hb Kempsey leads to
Over production of blood cells - Polycythemia
Hb Kansas
Cyanosis
alpha thalassemia
caused by deletion of one or both copies of the alpha-globin gene in the alpha cluster.
gamma and beta globin now in excess
alpha thalassemeias most common in Southeast asia
Hydrops Fetalis - - / - - ton of gamma 4
HbH disease a - / - - beta 4
mild anemia aa / - - alpha thalassemia - 1 trait
alpha thalassemias most common in Africa, Mediterranean, and Asia
mild anemia a - / a - alpha thalassemia - 2 trait
alpha thalassemeias most common in Southeast asia
Hydrops Fetalis - - / - - ton of gamma 4
HbH disease a - / - - beta 4
mild anemia aa / - - alpha thalassemia - 1 trait
alpha thalassemias most common in Africa, Mediterranean, and Asia
mild anemia a - / a - alpha thalassemia - 2 trait
As an adult how much HbA2 do you have?
What gene is mutated in Achondroplasia?
Fibroblast Growth Factor Receptor 3
FGFR3
Molecular basis of Achondroplasia?
Chromosome 4p16.3 nucleotide 1138
missense mutation Gly380Arg
Mutation increases the activity of the protein interfering with skeletal development
Mutation rate for Achondroplasia?
80%
Gonadal/germline mosaicism
The likely explanation of the rare situations where a person without a dominant condition can have two children with the same autosomal dominant condition
What is Retinoblastoma?
Malignant tumor of the retina
What is Neurofibromatosis Type 1
Mutation in the NF1 gene in Chromosome 17q11.2
Loss of function of a tumor suppressor gene NF1
Neurofibromatosis phenotype?
6 or more café-au-lait spots
2 or more neurofibromas
1 plexiform neurofibroma
2 or more Lisch Nodules
What is Neurofibromatosis Type 1
Mutation in the NF1 gene in Chromosome 17q11.2
Loss of function of a tumor suppressor gene NF1
Neurofibromatosis mutation rate?
50%
Osteogenesis Imperfecta Type 1 clinical manifestation
Multiple fractures
Mild short stature
Adult onset hearing loss
Blue sclera
Mutation that causes Osteogenesis Imperfecta Type 1
Collagen type 1 alpha 1 COL1A1 on Chromosome 7q21.3
Reduced production of pro-alpha 1 chains that reduces the type 1 collagen production by half
What is Marfan’s Disease?
Systemic disorder of connective tissue, musculoskeletal and cardiovascular problems.
Aortic Root enlargement seen!
Things to look for to diagnose Marfan’s Disease?
Thumb and wrist sign
scoliosis
ectopia lentis
pectus excavatum
What is the mutation involved in Marfan’s Disease?
Fibrillin gene FBN1 on Chromosome 15q21.1
What causes Huntington’s disease?
CAG repeats >39
Clinical manifestations of Huntington’s Disease
Progressive neuronal degeneration causing motor, cognitive and psychiatric disturbances
Age of onset 35-44
Death approximately 15 years after onset
Clinical manifestations of Huntington’s Disease
Progressive neuronal degeneration causing motor, cognitive and psychiatric disturbances
Age of onset 35-44
Death approximately 15 years after onset
What causes early Huntingtons onset?
Paternal transmission
Clinical manifestations of Myotonic Dystrophy Type 1
Adult onset muscular dystrophy Progressive muscle wasting and weakness Myotonia Cataracts Cardiac conduction defects
What causes Myotonic Dystrophy Type 1?
CTG repeat >50
Myotonic dystrophy protein kinase (DMPK) gene on Chromosome 19q13.3
How is Myotonic Dystrophy Type 1 transmitted?
Maternally!
What type of inheritance do metabolic diseases have?
Typically autosomal recessive
ex: PKU and Gaucher’s disease
Important use of DNA sequencing?
Ideal for looking at the sequence of a known disease gene
Can detect NOVEL mutations
