Step1Week2

7/27/2019 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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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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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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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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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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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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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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Familial hypercholesterolemia (HLP type

2A)


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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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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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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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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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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Neurofibromatosis 2 (NF2)


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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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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Von Hippel-Lindau disease


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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Cystic Fibrosis: this one is important


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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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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PKU


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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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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Hemophilia A


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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Hemophilia B aka Christmas Dz


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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G6PD (aka Favism)


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


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


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


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


Congenital microdeletion of short arm ofchromosome 5 (46 XX or XY, 5p-)


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


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

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