Genetics Review

Question 1

Codominance

Answer 1

Both alleles contribute to phenotype. Example is blood groups or A1AT deficiency

Question 2

Variable Expressivity

Answer 2

Where a phenotype varies in individuals with an given genotype. Example, NF1 (different disease severity with same mutation in ch 18

Question 3

Incomplete Penetrance

Answer 3

Where not everybody with a given mutation shows the phenotype. BRCA1 gene mutations don’t always cause cancer.

Question 4

Pleiotropy

Answer 4

One gene mutation can have many effects. PKU can have light skin, intellectual disability and musty body odor.

Question 5

Anticipation

Answer 5

Where a genetic disease passed down increases in severity or presents earlier. Trinucleotide repeats.

Question 6

Loss of heterozygosity

Answer 6

Essentially the two hit hypothesis. Loss of Rb doesn’t cause cancer, but loss of 2 does. This is shown with tumor suppressors, not oncogenes.

Question 7

Dominant Negative mutation

Answer 7

This is where a mutated allele asserts dominant effects over another normal allele. The mutation of a transcription factor in its allosteric site. Nonfunctioning mutants can still bind DNA preventing wild-type tfs from binding.

Question 8

Linkage Disequilibrium

Answer 8

In a population, the expected percentage of a phenotype due to independent assortment is altered because of two genes proximity on the chromosome. Genes can be inherited together. Can vary in different populations

Question 9

Mosaicism

Answer 9

Where errors in mitosis after fertilization cause multiple genotypes in different cells. This is different than lyonization because these cells have the same genotype. Somatic mosaicism is where the mutation propagates through multiple tissues or organs. Gonadal mosaicism is where a mutation is only in eggs or sperm cells to affect offspring.

Question 10

McCune Albright Syndrome

Answer 10

An example of mosaicism: a mutation in Gs-alpha subunit is survivable if mosaic, but not if somatic. Causes cafe-au-lait spots that do not cross the midline. Fibrous bones at the base of skull and in the femur.

Question 11

Locus heterogeneity

Answer 11

Mutations at different loci can cause similar phenotypes. Like albanism or mutations that cause marfanoid phenotypes.

Question 12

Allelic heterogeneity

Answer 12

Different mutations in the same locus produce the same phenotype. Like beta-thalassemia.

Question 13

Allelic heterogeneity

Answer 13

Different mutations in the same locus produce the same phenotype. Like beta-thalassemia.

Question 14

Heteroplasmy

Answer 14

The presence of both normal and mutated mitochondrial DNA allowing for different severities of a mitochondrial disease.

Question 15

Heteroplasmy

Answer 15

The presence of both normal and mutated mitochondrial DNA allowing for different severities of a mitochondrial disease.

Question 16

Uniparental Disomy

Answer 16

Where an offspring receives two copies of a chromosome from one parent and none from the other. Heterodisomy indicates a meiosis 1 error. Isodisomy is a meiosis 2 error. This is a euploid state and becomes important if a child is showing a recessive disease that only one parent is a carrier for.

Question 17

Hardy-Weinberg population genetics

Answer 17

A technique to analyze the frequency of a gene or genotype in a population assuming that mating is random, national selection isn’t occurring, no migration, and no mutation is occurring. P+Q=1 and P2+2PQ+Q2=1

P indicates the frequency of a particular allele.
P2 indicates the frequency of a particular genotype.

However, this all changes if the disease is X linked because it will be P for males and P2 for women.

Question 18

Imprinting

Answer 18

At some loci only one allele is active, the other is inactivated by methylation in a process called imprinting.

Question 19

Imprinting

Answer 19

At some loci only one allele is active, the other is inactivated by methylation in a process called imprinting. With one allele imprinted, the deletion of the active allele leads to disease.
Angelman syndrome or prader willi syndrome are examples. This can also occur as a result of uniparental disomy.

Question 20

Prader-Willi syndrome

Answer 20

Marental allele is imprinted, deletion of the Paternal allele on chromosome 15 leads to hyperphagia, intellectual disability, hypogonadism, and hypotonia. 25% of cases are due to maternal uniparental disomy where two maternally imprinted genes are received.

Question 21

Angelman Syndrome

Answer 21

Paternal gene is imprinted and maternal gene is deleted on chromosome 15. This results in the happy puppet phenomenon. Inappropriate laughter, seizures, ataxia, severe disability.

Question 22

How to tell if autosomal dominant?

Answer 22

All generations affected.

Question 23

How to tell if autosomal recessive?

Answer 23

Usually only one generation affected. Increased risk in inbreeding.

Question 24

How to tell if X-linked recessive?

Answer 24

Affected mother will pass mutation to all sons. Carrier mom will pass mutation to 50% of sons.

Question 25

How to tell if X-linked dominant

Answer 25

Father will pass mutation to all daughters but no sons. Mother will pass to 50% of sons.

Question 26

Hypophosphatemic Rickets

Answer 26

Example of an x-linked dominant disease. Inherited disorder that causes phosphate wasting at proximal tubule causing a rickets-like presentation.

Question 27

How to tell if mitochondrial inheritance?

Answer 27

Transmitted only through the mother, all offspring of affected female will have disease. Variable expression in a population or even a family due to heteroplasmy.

Question 28

Mitochondrial myopathies

Answer 28

Rare disorders with mitochondrial inheritance that cause myopathy, lactic acidosis and CNS disease. Usually due to a failure in oxidative phosphorylation. Ragged red fibers are the hallmark.

Question 29

List as many autosomal dominant diseases as possible

Answer 29

``` ADPKD FAP Familial hypercholesterolemia Hereditary hemorrgahic telangiectasia Hereditary spherocytosis Huntington's Marfan's ```

Question 30

List as many autosomal dominant diseases as possible

Answer 30

``` ADPKD FAP Familial hypercholesterolemia Hereditary hemorrgahic telangiectasia Hereditary spherocytosis Huntington's Marfan's MEN NF1 and NF2 Tuberous Sclerosis VHL Li-Fraumeni Syndrome. ```

Question 31

List as many autosomal dominant diseases as possible

Answer 31

``` ADPKD FAP Familial hypercholesterolemia Hereditary hemorrgahic telangiectasia Hereditary spherocytosis Huntington's Marfan's MEN NF1 and NF2 Tuberous Sclerosis VHL Li-Fraumeni Syndrome. ``` Asian, marfanoid hunter, named Li and his group of MEN went for a hunt. They had to get their own food because people were terrified of them: covered in NFs. On the hunt they slaughtered (hemorrhagic telangiectasia) of animals and ate their kidneys with a side of tubers. Because they only ate meat they had super high cholesterol. To end the night they all FAPs and watched people ball on VHS.

Question 32

ADPKD

Answer 32

An autosomal dominant mutation in PDK1 on chromosome 16 (polycystic kidney has 16 letters). Causes large kidney cysts, berry aneurysms, mitral valve problems. Can also be due to mutation in PKD2 on ch 4.

Question 33

FAP

Answer 33

Autosomal dominant mutation in APC gene on chromosome 5. Thousands of polyps in colon. 100% chance of cancer. This is a defect in WNT signaling, so every cell thinks its in an embryo and needs to divide.

Question 34

Familial hypercholesterolemia

Answer 34

Elevated LDL due to absent or mutated LDL receptor. Can causes LDL>300 or even >700. Normal is under 200. Can lead to atherosclerotic disease and MI in 20s. Xanthomas in achilles tendon.

Question 35

Hereditary hemorrhagic telangiectasia

Answer 35

AD disease of blood vessels leading to dilated vessels, epistaxis, skin discolorations and AVMs. Can also cause GI bleeding or hematuria. Also known as Osler-Weber-Rendu syndrome.

Question 36

Hereditary hemorrhagic telangiectasia

Answer 36

AD disease of blood vessels leading to dilated vessels, epistaxis, skin discolorations and AVMs. Can also cause GI bleeding or hematuria. Also known as Osler-Weber-Rendu syndrome.

Question 37

Hereditary spherocytosis

Answer 37

A AD mutation in ankyrin or spectrin leads to spherocytes. Spleen will eat blebs and therefore MCHC will increase. Eventually spherocytes will be destroyed by spleen leading to a normocytic anemia. Splenectomy is curative.

Question 38

Huntington Disease

Answer 38

A mutation in the huntingtin protein on chromosome 4 that causes accumulation and caudate atrophy. Causes chorea, severe disability. Trinucleotide repeat CAG. Decreased ACh and GABA in brain. Shows genetic anticipation.

Question 39

Marfan syndrome

Answer 39

Mutation in fibrillin 1 causes a connective tissue disorder that affects everything. Long extremities, tall, pectus excavatum, medial cystic degeneration predisposes to AAA and aortic dissections, floppy mitral valves. Lens subluxations

Question 40

MEN

Answer 40

Multiple endocrine neoplasias. MEN 2A and 2B are associated with mutations in the RET gene (also seen with Hirschsprung disease).

Question 41

MEN

Answer 41

Multiple endocrine neoplasias. MEN 2A and 2B are associated with mutations in the RET gene (also seen with Hirschsprung disease).

Question 42

NF1

Answer 42

Also known as Von Recklinghausen Disease. Defect in NF1 gene on chromosome 17. Causes cafe-au-lait spots, cutaneous neurofibromas, Wilms tumors, litsch nodules on retina.

Question 43

NF2

Answer 43

Associated with mutation in NF2 on chromosome 22. Hearing loss due to bilateral acoustic schwannomas.

Question 44

Tuberous Sclerosis

Answer 44

Neurocutaneous disorder characterized by multiple benign hamartomas and fatty kidneys (renal angiolipomas). Shows incomplete penetrance and variable expression.

Question 45

Von Hippel Lindau

Answer 45

Mutation in VHL tumor suppressor on chromosome 3. This leads to less ubiquitination of HIF causing angiogenesis. Causes hemangioblastomas and many other tumors.

Question 46

Li-Fraumeni Syndrome

Answer 46

Loss of p53 leads to many diseases.

Question 47

Li-Fraumeni Syndrome

Answer 47

Loss of p53 leads to many diseases.

Question 48

Autosomal Recessive Diseases

Answer 48

Albinism, ARPKD, CF, glycogen storage diseases, hemochromatosis, Kartagener syndrome, mucopolysaccharidoses (except hunter syndrome), phenylkentonuria, SCD, sphingolipidoses (except Fabry), thalassemias, Wilson's disease.

Question 49

CF

Answer 49

Mutation in CFTR on chromosome 7 where the protein is degraded before it reaches the membrane. Poorly folded at the RER and retained for degradation. Decreased Cl- (and therefore compensatory decrease in Na and then H2O) in lungs and pancreas, decreased reabsorption of Cl in salivary glands. Diagnose with sweat test (high cl). Can also cause hypovolemia because of renal H/K wasting and then loss of H2O and Na. Pseudomonas infections. Meconium ileus, ADEK deficiency, no vas deferens. Use N-acetylcysteine to break up mucus. Dornase alfa to clear leukocytic debris.

Question 50

X-linked recessive disorders

Answer 50

Brutons Agammaglubulinemia, Wiskott-adrich syndrome, Fabry's disease, G6PD deficiency, Ocular albanism, Lesch-Nyhan syndrome, Duchenne Muscular Dystrophy, Hunter Syndrome

Question 51

X-linked recessive disorders

Answer 51

Brutons Agammaglubulinemia, Wiskott-adrich syndrome, Fabry's disease, G6PD deficiency, Ocular albanism, Lesch-Nyhan syndrome, Duchenne Muscular Dystrophy, Hunter Syndrome, Hemophilia A and B, Ornithine Transcarbamylase deficiency.

Question 52

X-linked recessive disorders

Answer 52

Brutons Agammaglobulinemia, Wiskott-adrich syndrome, Fabry's disease, G6PD deficiency, Ocular albanism, Lesch-Nyhan syndrome, Duchenne Muscular Dystrophy, Hunter Syndrome, Hemophilia A and B, Ornithine Transcarbamylase deficiency. Be Wise, Fools GOLD Heeds silly HOpe. Female carriers affected variably due to X-inactivation.

Question 53

X-linked recessive disorders

Answer 53

Brutons Agammaglobulinemia, Wiskott-adrich syndrome, Fabry's disease, G6PD deficiency, Ocular albanism, Lesch-Nyhan syndrome, Duchenne Muscular Dystrophy, Hunter Syndrome, Hemophilia A and B, Ornithine Transcarbamylase deficiency. Be Wise, Fools GOLD Heeds silly HOpe. Female carriers affected variably due to X-inactivation.

Question 54

Duchenne's MD

Answer 54

X-linked recessive mutation in dystrophin gene. Frameshift leads to severely truncated protein that anchors cytoskeleton (actin) to extracellular matrix. Loss of dystrophin leads to myonecrosis. Diagnose with increased CPK and aldolase. This causes weakness in pelvic girdle muscles and progresses upwards. Pseudohypertrophy of calf muscles, patients use Gower maneuver. Onset before 5 years of age. Cause of death usually dilated cardiomyopathy.

Question 55

Becker's MD

Answer 55

Point mutation in dystrophin leads to less severe course. Onset in adulthood or adolescence.

Question 56

Myotonic Type 1

Answer 56

CTG repeat for DPMK gene leads to abnormal expression of myotonin protein kinase. Leads to myotonia, muscle wasting, frontal balding, cataracts, arrhythmia.

Question 57

Myotonic Type 1

Answer 57

CTG repeat for DPMK gene leads to abnormal expression of myotonin protein kinase. Leads to myotonia, muscle wasting, frontal balding, cataracts, arrhythmia.

Question 58

Fragile X Syndrome

Answer 58

Most common mental retardation after Down syndrome. Mutation affecting methylation of FMR. X-linked inheritance. Enlarged testes, long face with large jaw and everted ears, mitral valve prolapse. Trinucleotide repeat which is CGG.

Question 59

Fragile X Syndrome

Answer 59

Most common mental retardation after Down syndrome. Mutation affecting methylation of FMR. X-linked inheritance. Enlarged testes, long face with large jaw and everted ears, mitral valve prolapse. Trinucleotide repeat which is CGG.

Question 60

Trinucleotide repeat expasion diseases

Answer 60

Fragile X - CGG Friedrich Ataxia- GAA. Huntington's Disease - CAG Myotonic type 1 - CTG

Question 61

Trinucleotide repeat expasion diseases

Answer 61

Fragile X - CGG Friedrich Ataxia- GAA. Huntington's Disease - CAG Myotonic type 1 - CTG

Question 62

Trisomy 21 and 1st and 2nd trimester findings

Answer 62

Down Syndrome, 1:700. Intellectual disability, flat facies, prominent epithanthal folds, gap between first two toes, duodenal atresia, ASD, Hirschsprung disease, ALL. Alzheimer's disease. 95% due to meiotic nondisjunction (associated with advanced maternal age). 4% of cases due to robertsonian translocation. Findings: First trimester: Increased nuchal translucency hypoplastic nasal bone. Decreased PAPP-A. Free beta HCG is up. Second trimester: Decreased alpha fetoprotein, increased HCG, decreased estriol, increased inhibin A.

Question 63

Trisomy 18

Answer 63

Edwards Syndrome 1:8000. Severe intellectual disability, rocker bottom feet, micrognathia, low set ears. Death usually within 1 year. PAPP-A and bHCG are down in first trimester Quad screen: Decreased AFP, Decreased HCG, decreased estriol, decreased or normal inhibin A.

Question 64

Trisomy 13

Answer 64

Patau syndrome. Severe intellectual disability, rocker bottom feet, cleft lip/palate, holoprosencephaly, polydactyly. Death within 1 year. First trimester screen shows decreased HCG, decreased PAPPa, increased nuchal translucency.

Question 65

Robertson Translation

Answer 65

Nonreciprocal chromosomal translocation that involves pairs 13, 14, 15, 21, and 22. Long arms of acrocentric chromosomes fuse and short arms are lost. Balanced translocations usually don't cause trouble. Unbalanced translocations have problems.

Question 66

Cri-Du-Chat syndrome

Answer 66

Caused by a microdeletion of short arm of chromosome 5. Microcephaly, crys like cat, VSDs.

Question 67

Williams Syndrome

Answer 67

Deletion of long arm of 7. Causes extreme friendliness. Elfin faces.

Question 68

22q11 deletions

Answer 68

Cleft palate, abnormal facies, thymic aplasia, cardiac defects, hypocalcemia (due to parathyroid aplasia. CATCH 22 Degeorge is thymic, cardiac, hypocalcemia. Velocardiofacial - cleft palate, abnormal face, cardiac defects. Due to failure of 3 and 4 branchial pouches to develop.