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Transcript of Step1Week2
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Steven Katz, MSIV
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Genetics Terms
Basic Terms (Review) Gene:A hereditary unit consisting of a sequence of
DNA that occupies a specific location on achromosome and determines a particular
characteristic in an organism. Trait: A distinguishing feature, a genetically
determined characteristic or condition.
Allele: Versions of a gene
Genotype: Genetic makeup, distinguished from the
physical appearance. (G for genetic and genotype) Phenotype: The observable physical or biochemical
characteristics as determined by both geneticmakeup and environment
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Genetics Terms (cont.)
High Yield Terms: Classical Dominance: Dominant allele is
expressed if present
Incomplete Penetrance: Not all individuals with
a mutant genotype display the phenotype (manygenetics dzs but good example is NF1)
Variable Expression: Nature and severity ofphenotype changes between individuals
Co-dominance: Neither of two alleles is
dominant (e.g. blood types) Anticipation: Severity of disease worsens or age
of onset is earlier in succeeding generations(e.g. Huntingtons Dz)
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Genetics Terms (cont.)
High Yield Terms (cont.) Loss of heterozygosity: When a tumor
suppressor gene is mutated or deleted, thecomplimentary allele must be lost before a
cancer develops. Not true with oncogenes! Dominant negative mutation: a non-functioningprotein also prevents a normal protein fromfunctioning appropriately (e.g Marfanssyndrome)
Heteroplasmy: Both NL and mut mtDNA resultsin variable expression in mitochondrial inheriteddzs
Uniparental disomy: offspring receives 2 copiesof a chromosome from 1 parent and none fromthe other
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Imprinting
Definition: At a single locus, only one allele isactive, the other is inactive; can also occur asa result of uniparental disomy Phenotype depends on origin of mutation paternal
v. maternal
Both syndromes due to inactivation or deletionof genes on chromosome 15
Prader-Willi: Deletion of normally activePATERNAL allele Mental retardation, obesity, hypogonadism,
hypotonia Angelmanssyndrome (aka Happy Puppet
Syndrome): Deletion of normally activeMATERNAL allele Mental retardation, seizures, ataxia, innapropriate
laughter
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Modes of Inheritance
Autosomal Dominant: Affects both males and
females in all generations. Presents clinically after
puberty and FH is essential for diagnosis.
Examples: Achondroplasia, Huntingtons dz,
Neurofibromatosis types 1 & 2, and many manymore!
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Modes of Inheritance
Autosomal Recessive: only offspring of 2carrier parents can be affected. Usually onlyseen in one generation, usually due to enzymedeficiencies.
Commonly more severe than dominant disorders,presents in childhood
Examples: Albinism, Cystic Fibrosis, PKU, Wilsonsdz, and many more!
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Modes of Inheritance
X-linked recessive: only sons ofheterozygous mothers can be affected, nofather to son transmission. Examples: Fragile X, Lesch-Nyhan, Hemophilia
A and B
Females may rarely be affected due to randominactivation of X chrom (e.g. Lyonization)
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Modes of Inheritance
X-linked dominant: Transmitted throughboth parents, males and females can beaffected, but all females of affected fathersare affected. Example-
Hypophosphatemic rickets: increased phosphatewasting at proximal tubule
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Modes of Inheritance
Mitochondrial: Transmission ONLYthrough the mother. All offspring ofaffected mothers are affected.
Variable expression due to heteroplasmy
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Autosomal Dominant Dzs
Achondroplasia Genetics and Cell Level:
Defect in Fibroblast Growth Factor receptor 3 Causes abnormal cartilage development
Phenotypic Traits:
Dwarfism: short limbs, head and neck nl size
Misc info:
Associated with advance paternal age
AD so if one parent affected then 50% of childrenaffected
Homozygotes die either before or shortly afterbirth
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Autosomal Dominant Dzs
APKD (adult polycystic kidney dz) Genetics and Cell Level:
90% due to mut in APKD1 on chromosome 16
Phenotypic Traits:
Bilateral enlargement of kidney due to multiplecysts
Clinical Presentation: b/l flank pain, hematuria,HTN, progressive renal failure
Usually presents in adulthood (hence the name!) Misc info:
Associated with polycystic liver dz, berryaneurysms, MVP
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APKD
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Autosomal Dominant Dzs
Familial Adenomatous Polyposis
Genetics and Cell Level:
Deletion on chromosome 5q21-22 (APC gene)
Phenotypic Traits: Colon covered with polyps after puberty that
progress to cancer if not resected
Clinical Presentation: anemia, melena,
changes in bowel habits Misc info:
Will need colonoscopies early and often
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FAPCC
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Autosomal Dominant Dzs
Familial hypercholesterolemia (HLP type
2A)
Genetics and Cell Level:
Defective or absent LDL receptor
Heterozygotes (1:500) ~ 300 mg/dl
Homozygotes (very rare) ~ 700+ mg/dl
Phenotypic Traits:
Xanthelasma palpebrarum, tendon xanthomas
(classically on the Achilles tendon), severe
atherosclerotic dz, MI may develop early
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Familial Hypercholesterolemia
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Autosomal Dominant Dzs
Huntingtons Disease Genetics and Cell Level:
Gene located on Chromosome 4, trinucleotiderepeat disorder (CAG)n
Decreased levels of GABA and Ach in the brain Clinical Presentation: depression, progressive
dementia, choreiform movements, caudateatrophy Usually presents between the ages of 20 to 50
Misc info: Age of onset is variable but typically the more
repeats you have the earlier the onset of thedisease
Watch out for ethical issues!
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Autosomal Dominant Dzs
Marfans Syndrome Genetics and Cell Level:
Mutation in the fibrillin gene (Chrom 15)
Phenotypic Traits:
Connective tissue disorder affecting skeleton,heart, and eyes
Clinical Presentation: tall with long extremities,pectus excavatum, hyperextensive joints, andlong tapering fingers and toes
Misc info: Cystic medial necrosis of the aorta leads to aortic
incompetence and dissecting aortic aneurysms
Floppy mitral valve
Subluxation of lenses
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Marfans Syndrome
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Autosomal Dominant Dzs
Multiple Endocrine Neoplasia (MEN)
Type 1 Type 2a Type 2b
Eponym Wermers syndrome Sipple Syndrome MEN 3 (old name)
Clinical Pancreatic tumors,
Parathyroid
adenoma, Pituitary
hyperplasia
Parathyroid
hyperplasia, Medullary
thyroid carcinoma,
phechromocytoma
Medullary thyroid
carcinoma,
phechromocytoma,
marfanoid habitus,
mucosal neuromasGene MEN1 RET proto-oncogene RET proto-
oncogene
Misc Spontaneous
mutation rate ~50%
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Autosomal Dominant Dzs
Neurofibromatosis 1 (NF1/vonRecklinghausens dz) Genetics and Cell Level:
Mutation on chromosome 17q11 (long arm of17)
Clinical Presentation: caf-au-lait spots,neural tumors, Lisch nodules (pigmented irishamartomas)
Misc info:
Increased incidence of pheochromocytomas,susceptibility to tumors, and skeletal disorders
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NF1
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Autosomal Dominant Dzs
Neurofibromatosis 2 (NF2)
Genetics and Cell Level:
Mutation on chromosome 22q12
Clinical Presentation: bilateral acousticneuromas on CN8, juvenile cataracts
Tumors may cause tinnitus, HA, hearing loss,
balance problems, vertigo, etc.
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Autosomal Dominant Dzs
Tuberous Sclerosis Genetics and Cell Level:
Incomplete penetrance, 2/3 of new casesarise from spontaneous mutations
Clinical Presentation: facial lesions(adenoma sebaceum), hypopigmented ashleaf spots, cortical and retinal hamartomas,seizures, mental retardation, renal cysts and
angiomyolipomas, cardiac rhabdomyomas,increased incidence of astrocytomas
Misc:
Needless to say presentation is VERYvariable
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Tuberous Sclerosis:
Ash Leaf Spot
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Autosomal Dominant Dzs
Von Hippel-Lindau disease
Genetics and Cell Level:
Deletion of VHL gene (tumor suppressor) on
chromosome 3, results in expression of HIF and
activation of angiogenic growth factors
Phenotypic Traits:
Hemangioblastomas of retina/cerebellum/medulla
About of affected develop multiple b/l renal cell
carcinomas and other tumors
Clinical Presentation: miscellaneous can be
discomfort from growing tumors or blindness 2/2
tumors in retina
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Autosomal Recessive Dzs
a1-antitrypsin deficiency Genetics and Cell Level:
Serine protease inhibitor important for elastase
Clinical Presentation: COPD and cirrhosis inearly adulthood
Misc:
Important when presented with pt who has COPDsxs and has only smoked for a few years
PiMM: 100% (normal)
PiMS: 80% of normal serum level of A1AT PiSS: 60% of normal serum level of A1AT
PiMZ: 60% of normal serum level of A1AT
PiSZ: 40% of normal serum level of A1AT
PiZZ: 10-15% (severe alpha 1-antitrypsin deficiency)
PiZ is caused by a glutamate to lysine mutation at position 342
PiS is caused by a glutamate to valine mutation at position 264
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Autosomal Recessive Dzs
Cystic Fibrosis: this one is important
Genetics and Cell Level:
CFTR gene mutation on chrom 7 DF508classically (loss of phenylalanine)
Defective Cl channel
Clinical Presentation: secretion of abnl thickmucus into lungs, pancreas, and liver
Pulm infections (P. aeruginosa and S. aureus)
Chronic bronchitis, bronchiectasis, pancreaticinsufficiency, male infertility (absence of vasdeferens)
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Autosomal Recessive Dzs
Cystic Fibrosis (cont.)
Diagnosis:
increased concentration of Cl in sweat test
Treatment: N-acetylcysteine to loosen mucus plugs
Misc:
If presented with . . . THINK CF!
newborn with meconium ileus or failure to thrive
Fat soluble vitamin deficiency
Pancreatic insufficiency
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Autosomal Recessive Dzs
PKU
Genetics and Cell Level:
Defect in phenylalanine hydroxylase which
converts Phe to Tyr Clinical Presentation: Mental retardation,
seizures, albinism, musty odor to urine and
sweat
Misc: Very treatable diet low in Phe and high in Tyr
Newborn screening is Mandatory!
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Autosomal Recessive Dzs
Sickle Cell Disease Genetics and Cell Level:
Point mutation in Beta-globin chain Glutamic acid to Valine
Clinical Presentation: Heterozygotes usually clinically silent but added
protection to malaria
Homozygotes: symptoms are complications ofsickled RBC must be vaccinated against S.pneumo before loss of spleen Hyposplenism, vaso-occlusive crises, many other
complications including priaism, stroke, etc.
Misc: Parvovirus B19 can cause aplastic crisis
Treatment: Hydroxyurea, Folic acid, pain controlfor vaso-occlusive crises
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X-Linked Recessive Dzs
Fragile X (most common inherited form of retardation) Genetics and Cell Level:
Expansion of CGG on chrom X (FMR1 gene), full mutation is >200 repeats
Associated with chromosomal breakage (hence the name)
Clinical Presentation
Mental retardation ranges from mild to severe Also autism, elongated face, large or protruding ears, flat feet,macroorchidism, and low muscle tone
Fragile X = eXtra-large testes, jaw, and ears
Misc: Presentation is variable but si/sx fall into six classiccategories Intelligence and learning
Physical Social and emotional
Speech and language
Sensory
Disorders commonly associated or sharing features with FragileX
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X-Linked Recessive Dzs
Hemophilia A
Genetics and Cell Level:
Loss of Factor VIII
Clinical Presentation: Increased PTT butnormal PT and bleeding time
Bleeding can occur into many sites most
common are joints, brain, muscles, and GI
tract Treatment is with Factor VIII
If dz is caused by low levels of Factor VIII and
not loss then desmopressin can be used
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X-Linked Recessive Dzs
Hemophilia B aka Christmas Dz
Genetics and Cell Level:
Loss of Factor IX
Clinical Presentation: Increased PTT butnormal PT and bleeding time
Bleeding can occur into many sites most
common are joints, brain, muscles, and GI
tract REVIEW THE CLOTTING CASCADE
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X-Linked Recessive Dzs
G6PD (aka Favism)
Genetics and Cell Level:
Defect in glucose 6-phosphatedehydrogenase
Clinical Presentation:
Prolonged neonatal jaundice can becomplicated by kernicterus
Acute hemolytic anemia in the presence of
simple infection, fava beans, or rxn withcertain medicines (antibiotics, antipyretics,and antimalarials)
Misc: Look for Heinz bodies on peripheral
smear in active process
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G6PD
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Muscular Dystrophies
Duchennes Genetics and Cell Level:
Frame shift mutation in dystrophin gene (DMD)leads to deletion and accelerated muscle
breakdown. Dystrophin anchors muscle fibers, primarily
skeletal and cardiac muscles
Clinical Presentation: Dx by increased CPK andmuscle biopsy, onset before age 5
Weakness begins in pelvic girdle and progressessuperiorly
Pseudohypertrophy of calf muscles 2/2 fibrofattyreplacement of muscle
Misc: Look for use of Gowers maneuver
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Gowers maneuver
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Muscular Dystrophies
Beckers
Genetics and Cell Level:
Defect in dystrophin gene, less severe than
Duchennes defect Clinical Presentation:
Progressive muscle weakness, onset later
than Duchennes
Misc: dx is similar to Duchennes
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Autosomal Trisomies
Down Syndrome (Trisomy 21) Most common chromosomal disorder and most
common cause of congenital mental retardation
Diagnosis done by triple screen
decr. a-fetoprotein, estriol, incr. b-hCG
Quad screen is above plus inhibin A (incris +)
U/S shows increased nuchal translucency
Clinical Presentation:
Mental retardation, flat facies, prominentepicanthal folds, simian crease, duodenal atresia,congenital heart dz (septum primum type ASD),hypotonia
Misc: increased risk of ALL and Alzheimer's dz
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Autosomal Trisomies
Down Syndrome (Trisomy 21) (cont.)
95% of cases due to meiotic nondisjunctionof homologous chromosomes
Associated with advanced maternal age 1:1500 at maternal age 20-24
1: 210 at maternal age 35-39
1: 25 at maternal age >45
4% of cases due to Robertsonian
translocation Long arm of chrom 21 is attached to another
chromosome and is kept diploid duringgametogenesis
1% of cases due to Down mosaicism
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Down Syndrome
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Autosomal Trisomies
Edwards Syndrome (Trisomy 18)
Edwards = Eighteen
Most common trisomy in live birth after
Down syndrome (1:8000) Clinical Presentation:
Severe mental retardation, rocker-bottom feet,
micrognathia, low-set ears, clenched hands,
prominent occiput, congenital heart dz
Misc: Death usually within one year of age
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Autosomal Trisomies
Pataus Syndrome (Trisomy 13)
Incidence is 1:15000
Clinical Presentation:
Severe mental retardation, rocker-bottom feet,microphthalmia, microcephaly, cleft lip/Palate,
holoProsencephaly, Polydactyly, congenital
heart dz (anyone see a theme??)
Misc: Death usually within 1 year of birth
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Nondisjunction
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Cri-du-Chat syndrome
Genetics and Cell Level:
Congenital microdeletion of short arm ofchromosome 5 (46 XX or XY, 5p-)
Clinical Presentation:
Microcephaly, moderate to severe mentalretardation, epicanthal folds, cardiacabnormalities
Misc: Cri-du-chat is French for cry of the cat.
The disease is named this way as thechildren affected make a high pitchedmewing/crying sound.
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Williams syndrome
Genetics and Cell Level:
Congenital microdeletion of long arm of
chromosome 7 (46 XX or XY, 7q-) which
includes the elastin gene Clinical Presentation:
Distinctive elfin facies, mental
retardation, well-developed verbal skills,
cheerful disposition, extreme friendliness
with strangers, cardiovascular problems
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22q11 deletion syndromes
Variable presentation includes
Cleft palate
Abnormal facies
Thymic aplasia which leads to T-celldeficienies
Cardiac defects
Hypocalcemia 2/2 parathyroid aplasia
CATCH-22
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22q11 deletion syndromes
Aberrant development of 3rd and 4th
branchial pouches
DiGeorge Syndrome:
Thymic, parathyroid (hypocalcemia), andcardiac defects
Cardiac defects include Tetralogy of Fallot, VSD, and
perisistent truncus arteriosus
Velocardiofacial syndrome: Palate, facial, and cardiac defects
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Hardy-Weinberg Genetics
If a population is in HW equilibrium and pand q are separate alleles then Disease prevalence: p2 + 2pq + q2 =1
Allele prevalence: p +q = 1
2pq = heterozygote prevalence The prevalence of an X-linked recessive dz in
males = q and in females is q2
Hardy-Weinberg laws1. No mutation occurring at the locus
2. No selection for any of the genotypes at thelocus
3. Completely random mating
4. No migration