Genetics Flashcards
what are genes
hereditary units of DNA transmitted from one generation to another, basically they are codes for the production of proteins
what is a Locus
what is an allele
the specific location of a gene on a chromosome
alleles are different versions of. a gene
human alleles
humans have 2 alleles for each autosomal gene
chromosomes
structure composes of genes located in the nucleus of a cell
they are distinguished from each other by length and the position of the centromere
homologous chromosomes
have the same genes on the same loci one is maternal and one is paternal
hw many chromosomes do human somatic cells have
46 total chromosomes made of 23 pairs
23 from mom23 from dad
mutations
can be spontaneous or induced by exposure to mutagenic chemicals or radiation
the effects vary and depend on where in the gene code the mutation has occurred
net result of a mutation
can be a physical. appearance or some other trait, again depending on the location
allosome pair
the sex chromosome pair, all other 22 pairs are autosome chromomosemes
p arm, r arm
in human chromosomes the short are is the p arm and the long arm is the q arm
what determines maleness
genetic factors on the Y allosome
mitosis involves which cells
somatic, creates an exact copy through division creates two daughter cells
meiosis
produced gametes have 23 new chromosome pairs with new combos of the original maternal and paternal copies
only occurs in germ cells in the gonads
consist of two consecutive cell divisions producing cells with half he number diploid to haploid
co dominance example
when two alleles for a trait are equally expressed AB blood type
an allele lacks complete dominant and restive relationships and both are observed
incomplete dominance
heterozygotes have phenotypes that have both alleles visible as a blend
creates a third phenotype
human ex- wavy hair, skin color
penetrance
probability that individuals in a population who have a particular gene combination will show the condition
functions of 3 generation pedigree
Making a diagnosis Deciding on testing strategies Establishing the pattern of inheritance Identifying people at risk Educating the patient Determining reproductive options
pedigree language
male square female circle
Diagonal line through symbol – deceased Shaded symbol – affected with trait
Half-shaded symbol – carrier of trait
Consultand
The person seeking genetic advice
Can be healthy or a person with a condition
proband
the affected individual
autosomal dominant
65% of human monogenic disorders
mutations at just a single allele can cause a disease in an individual
autosomal dominant example
Huntington’s disease
characteristics of Autosomal Dominant disorders
vertical pattern multiple generations are affected
expressivity may be variable
some with the makeup may not show the phone type
males and females equal
male to male transmission seen
autosomal recessive
25% of human monogenic disorders
tend to envolve enzymes or receptors
rare
often seen in consanguinity
autosomal recessive example
cystic fibrosis
x linked
5% of human monogenic disorders
males more likely to develop both D and R
D and R only apply to females
all daughters of an affected male are heterozygous carriers
males usually more severely affected than females
x linked heterozygous females usually are
normal or mild
x linked male to male transfer
is not possible
unaffected makes do not transmit the phenotype
x linked dominant examples
aport’s syndrome, fragile X syndrome
x linked recessive example
wiskott aldrich syndrome
Duchenne muscular dystrophy
Multifactorial/Complex Disease examples
Cancer Diabetes Asthma Heart disease Mental illness Cleft lip/cleft palate
need an environmentally factor to turn on gene, meet threshold for phenotype to show
Down syndrome
trisomy 21, most common chromosomal abnormally in live births
gamut has two copies of chromosome 21
leads to trisomy when it is fertilized
1 in 500 pregnancies
pre natal testing for Down syndrome
quad screen and nuchal translucency
what else can cause Down syndrome
4% f cases are due to roberystonian translation, this would require us to do parental chromosome studies
Down syndrome characteristics
intellectual disability, facial appearance, 40% cardiac defects 75% hearing loss less than 50% have visual problems and 7% have GI defects
increased social skills in childhood
Edwards syndrome
trisomy 18, second most common autosomal trisomy that goes to full term
translocation can cause this disorder
many will die before birth or first month
1:5000 live births
IUGR
highly lethal in utero 85% are lost between week 10 to term
50% die in first week of life
2% 1 year survival rate
heart go and kidney defects
Edwards syndrome characteristics
kidney and. heart defects, developmental delays club foot rocker bottom feet
low set ears small jaw
patau syndrome
trisomy 13 1:16000 live births Severe intellectual disability Many physical abnormalities Cleft lip or palate Seizures Small jaw Polydactyly Heart defects, brain/spinal cord abnormalities Many children die within first days or weeks of life
patau syndrome and translocation
Some caused by Robertsonian translocation involving chromosomes 13 and 14
When a part of chromosome 13 gets attached to chromosome 14 during formation of gametes
Affected people have 2 normal copies of 13 plus an extra copy attached to another chromosome
Cri-du-Chat Syndrome
chromosomal abnormality deletion of part of short arm on chormose 5
Cat-like cry of affected children due to abnormal larynx development
Intellectual disability, wide set eyes, low ears
1 in 50,000 births
Can be detected in utero with CVS
Klinefelter’s Syndrome
Extra X chromosome, 47 XXY
Occurs during gametogenesis
Affects male physical and cognitive development
Accounts for many first trimester losses
Physical traits become more apparent after puberty
Most common sex chromosome aneuploidy in males
Hypogonadism, infertility
Gynecomastia, reduced hair
Turners syndrom
45 X, affects development in females Gonadal dysgenesis Non-functional ovaries Short stature Broad chest Webbed neck Amenorrhea Infertility Cardiovascular abnormalities
Huntington’s Disease
A neurodegenerative disease
Causes uncontrolled movements, emotional problems, and loss of thinking ability, changes in personality
Early signs: depression, irritability, poor coordination, trouble learning
chorea
Adult onset: genetic defect is latent for 3-5 decades, then manifests as progressive neuronal dysfunction
Huntington’s Disease Pathophysiology
HD gene on chromosome 4 that codes for a unique protein called huntingtin
CAG trinucleotide repeat
Normal: 10-35 repeats
In HD: 36-120 repeats
causes microscopic deposits of protein in neurons
Average time from symptom onset to death is 15 years
Huntington’s Disease inheritance
Only human disorder of complete dominance
Heterozygotes are just as affected clinically as homozygotes
Alzheimer’s Disease
A neurodegenerative disease
Most common form of dementia in older individuals
Usually begins after age 60; risk increases with age
Death usually occurs within 10 years
People with parent, sibling, or child with AD are at increased risk
Progressive mental deterioration: memory loss, confusion,
disorientation
dementia forms
65% from Alzheimer’s Disease
35% vascular in nature
Alzheimer’s Disease Pathophysiology
loss of acetylcholine causes Formation of plaques and tangles
Atrophy of brain
Resultant effect – blocked communication
Several gene mutations cause predisposition to AD
Alzheimer’s late vs early onset
familial early onset
sporadic late onset
early onset
Many members of multiple generations affected Symptoms start before age 65 Mutations on chromosomes 1, 14, or 21 Induce formation of a “sticky” protein Rare - <5% of cases of AD Autosomal dominant
Sporadic Alzheimer’s Disease
One gene has been shown to increase risk
Chromosome 19 apolipoprotein E (APOE) gene Not everyone carrying the gene develops disease
Definitive diagnosis: autopsy-plaques and tangles
Hereditary Breast and Ovarian Cancer Syndrome risk factors
gender age and family history
up to 10% of breast and ovarian cancers are caused by known predisposing genetic factors
Hereditary Breast and Ovarian Cancer Syndrome Genetic testing
Preferable to first test an individual who is affected by cancer before testing unaffected family members
Helps to identify whether a detectable BRCA1 or BRCA2
An individual can inherit a BRCA1 or BRCA2 mutation yet never develop cancer
colorectal cancer
Genetic predisposition is the main risk factor in only a small proportion of people
Diet, exercise, smoking, obesity are stronger risk factors in most people
familial colorectal cancers
Patterns within a family that exist without identifying a specific mutation
A family history of one or more people with colorectal cancer or premalignant polyps
familial colorectal cancers may be due to
Chance alone
Shared exposure to a carcinogen or diet/lifestyle factors
Combination of gene mutations and environmental risk factors
Familial adenomatous polyposis (FAP)
autosomal dominat
genetic mutation at APC (adenomatous
polyposis coli) gene
polyps in colon begin forming in adolescence
APC is a tumor suppressor gene on chromosome 5
when it is mutated it allows for cancers to develop in 20s
risk of developing colorectal cancer is near 100% usually before age 50
Time from polyp to cancer development is 10+ years
genetic cosseting and testing for FAP
should be offered to all patients with suspected diagnosis of FAP after colonoscopy and to relatives at risk
children should have the screening by 10 years of age
recommendation for those with established FAP
total colectomy before age 20
hereditary nonpolyposis colorectal cancer
HNPCC / Lynch syndrome
2-3% all colorectal cancers
autosomal dominant
mutation in many genes that code for DNA repair
more rapid transition from adenoma to cancer than FAP
cancers occur earlier 30 and 40s
can occur with small number or no polyps present
associated with formation of other cancers such at uterus ovaries stomach UT small bowl and bile ducts
hereditary nonpolyposis colorectal cancer men vs women
50% chance of cancer in women and 70% in men
genetic testing HNPCC
if mutation is found
it is recommended that regular colonoscopy start at age 25 for relatives or 5 years younger than the youngest that those diagnosed
upper endoscopy every two years to screen for gastric cancer
screening for endometrial and vain cancer in women at age 25 to 35
chronic myelogenous leukemia
myeloproliferative disorder (blood cancer)
more common in men
55 years old median age for presentation
translocation between chromosomes 9 and 22
Philadelphia chromosome
chromosome 22
produces a protein that codes doe an enzyme that causes too many stem cells to develop into WBCs
chronic myelogenous leukemia pathophysiology
increased production of abnormal white blood cells that are none functional and take up bone marrow space that is meant for WBC RBC and platelets
chronic myelogenous leukemia clinical presentation
insidious onset slow progression over months or years
infection anemia bleeding fever night sweat fatigue
chronic myelogenous leukemia diagnosis
bone marrow aspiration for karyotype
hemophilia
bleeding disorder cause by mutation in genes that code for coagulations proteins
mutations on F8 or F9 on the X sex chromosome
x linked recessive
hemophilia mutations (2)
F8 causes VIII deficiency causing the more common hemophilia A
F9 causes IX deficiency causing hemophilia B or Christmas disease
hemophilia clinal manifestations
hemarthrosis, bleeding into muscle and soft tissue, prolonged bleeding or oozing
severity is variable
sickle cell disease pathophysiology
atypical hemoglobin molecules (S) distorts red blood cells in to present or sickle shape causing RBC to break down prematurely
the mutation occurs on HBB gene
sickle cell disease clinical manifestations
anemia, infections, episodic pain, SOB, fatigue delayed growth
sickle cell disease
autosomal recessive
more common in people whose ancestors came from Greece Africa turkey Italy
cystic fibrosis
autosomal recessive mutation in the CFTR (regulator) gene this gene codes for a protein that regulates chloride channels in epithelial cells when it is mutated the protein is defective and there is a disruption in the chloride and water transport and water balance in secretions is disrupted common in white population in the US 1 3500 white newborns 1 in 25 are carriers diagnosed by age 1
cystic fibrosis clinical manifestations
Causes thick, sticky mucous obstructing airways in lungs and
ducts in pancreas
difficult breathing, infections in lungs
cystic fibrosis Problems with nutrient digestion
Buildup of mucous prevents pancreatic enzymes from reaching intestine
Failure to thrive, poor growth rate
Meconium ileus – newborn intestinal obstruction due to thick
fecal waste products
most common morbidity associated with CF
pulmonary disease
Pulmonary system can’t defend against pathogens well – leads to sinusitis and bronchitis
Most common organisms: S. aureus, P. aeruginosa, Aspergillus Nasal polyps, nosebleeds, chronic sinus infections common in
CF patients
Thick mucous builds up in lower airways causing obstruction
sweat chloride test
primary test for CF diagnosis
Defective chloride channel doesn’t allow chloride to be
reabsorbed
Concentration of chloride in sweat is elevated in CF
Genetic testing used to confirm results
marfans syndrome
autosomal dominant
inherited muslin or a new mutation of the fibrillar -1 gene
defects are seen in the connective tissue of bones ligaments muscles blood vessels and heart valves
marfans syndrome clinical manifestations
tall stature arm span wider than body height long narrow face high arched palate over crowed teeth scoliosis hyperflexible joints chest deformities
marfans syndrome key featurs
dislocation of the lens of the eye
aortic aneurysm and dissection
heart defects are major causes of morbidity and morality
mitral valve prolapse and aortic valve regulation
= SOB fatigue palpitations
those with marfans should avoid contact with
sports caffeine and decongestants due to increased stress placed on CV system
Neurofibromatosis Type I
Von Recklinghausen disease, autosomal dominant
mutation on NF1 gne on chromosome 17, most common
a tumor suppressor gene
results in growth of neurofibromas and skin pigmentation changes cafe au last spots
lisch nodules in iris
freckles in axillae and groin
neurofibromas
benign tumors that grow on nerves of skin and brain
2 or more for diagnosis of Neurofibromatosis Type I
Crowe sign
axillary or inguinal frecking
neurofibromas diagnostic features
1.5 cm or larger café-au-lait spot post puberty or 6 or more café-au-lait spots 0.5 cm or larger in before puberty
2 or more neurofibromas
Axillary or inguinal freckling (Crowe sign)
Optic glioma
2 or more Lisch nodules
1st degree relative with NF1
polycystic kidney disease
Clusters of fluid filled sacs develop in kidneys, this affects ability to filter the blood properly. kidneys become enlarged and can fail
polycystic kidney disease clinical manifestations
hypertension, back pain, hematuria, UTIS kidney stones
polycystic kidney disease other associations
liver cysts, heart valve abnormalities, increased aortic aneurysm and brain aneurysm
polycystic kidney disease forms
Autosomal dominant – sx start in adulthood 1 in 1000; PKD1 and PKD2 genes
Usually inherited (90% of the time)
Autosomal recessive – rare, lethal early in life 1 in 30,000
PKHD1 gene
Approximately _____% of all newborns have some birth defect
10%
Ranges from minor biochemical problem to severe physical deformity
Caused by variety of biological, chemical, and physical agents
Contributors: mutant genes, chromosomal defects, multifactorial components
biggest cause of birth defects
unknown etiology
Teratology
study of abnormal development
Teratogens
nything capable of disrupting embryonic or
fetal development and producing malformations
critical period for
teratogenic effects is 3-16 weeks
timing of exposure determines which systems are affected
CNS development vs teeth and palate development in utero
CNS begins to develop in 3rd week, while teeth and palate begin to form in 6th-7th week
new born screening
Biochemical analysis that determines whether certain proteins (enzymes) are present or absent
typically autosomal recessive conditions
“inborn errors of metabolism”
Inherited defect in one or more enzymes
law 2008 increased uniform testing
first test at 24-36 hours old next at 5 to 10 days
