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STEP 1 (4) > Biochemistry-Genetics > Flashcards

Biochemistry-Genetics Flashcards

1
Q

What is codominance?

A

both alleles contribute to the phenotype of the heterozygote (e.g. blood groups A, B, AB)

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2
Q

What is variable expressivity?

A

phenotype varies among individuals with the same genotype (2 pts. with neurofibromatosis type I (NF1) may have varying disease severity)

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3
Q

What is incomplete penetrance?

A

not all individuals with a mutant genotype show the mutant phenotype (e.g. BRCA gene mutations do not always result in breast or ovarian cancer)

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4
Q

What is pleiotropy?

A

when one gene contributes to multiple phenotypic effects (e.g. untreated PKU manifests with light skin, intellectual disability, and musty body odor)

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5
Q

What is anticipation?

A

increased severity or earlier onset of disease in succeeding generation (.e.g Huntington disease)

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6
Q

Describe loss of heterozygosity

A

if a pt inherits or develops a mutation in a tumor supressor gene, the complementary allele must be deleted/mutated before cancer develops. THis is not true of oncogenes (i.e. two hit theory)

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7
Q

What are dominant negative mutations?

A

exerts a dominant effect. A heterozygote produces a nonfunctional altered protein that also prevents the normal gnee product from functioning

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8
Q

What is linkage disequilibrium?

A

tendency for certain alleles at 2 linked loci to occur together more or less often than expected by change. Measured in a population, not in a family, and often varies in different populations

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9
Q

What is heteroplasmy?

A

presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrially inherited disease

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10
Q

What is allelic heterogeneity?

A

different mutations in the same locus produce the same phenotype (i.e. B-thalassemia)

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11
Q

What is locus heterogeneity?

A

different mutations in the same locus produce the same phenotype (i.e. albinism)

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12
Q

What is mosaicism?

A

presence of genetically distinct cell lines in the same individual

Somatic mosaicism- mutation arises from mitotic errors after fertilization and prpagates through mutliple tissues or organs

Gonadal mosaicism- mutation only in egg or sperm cells

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13
Q

What is McCune-Albright Syndrome?

A

due to mutations affecting G-protein signaling. Presents with unilatera cafe-au-lait spots, polyostotic fibrous dysplasia, precocious puberty, and multiple endocrine abnormalities

lethal if mutation occurs before fertilization (affecting all cells), but survivable in pts with mosaicism

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14
Q

What is uniparental disomy?

A

When an offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent.

Heterodisomy (heterozygote) indicates a meiosis I error

Isodisomy (homozygous) indicates a meiosis II error or postzygotic chromosomal duplication of one of a pair of chromosomes, and the loss of the other of the original pair

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15
Q

Example of uniparental disomy

A

Uniparental is eUploid (correct number of chromosomes), not aneuploid. Most occurences of UPD leads to normal phenotypes. Consider UDP in an individual manifesting in a recessive disorder when only one parent is a carrier

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16
Q

If a population is in Hardy-Weinberg equilbrium and if p and q are the frequencies of seperate alleles, then: p2 + 2pq + q2= 1 and p+q=1 which implies that:

p2= frequency of homozygosity for allele p

q2= frequency of homozygosity for allele q

2qp= frequency of heteroxygote

A
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17
Q

In Hardy-Weinberg equilbrium, the frequency of an X-linked recessive disease in males=

A

q, and in females = q2

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18
Q

Hardy- Weinberg law assumptions:

A

No mutation occuring at the locus

Natural selecction is occurring

Completely random mating

No net migration

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19
Q

What is imprinting?

A

At some loci, only one allele is active; the other is inactive (imprinted/inactivated by methylation). With one allele inactivated, deletion of the active allele causes disease

E.g. both Prader-Willi and Angelman syndromes are due to mutation or deletion of genes on chromosome 15

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20
Q

What is Prader Willi syndrome?

A

maternal imprinting disease where the gene from mom is normally silent and the paternal gene is deleted/mutated resulting in:

hyperphagia, obesity, intellectual disability, hypogonadism, and hypotonia

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21
Q

25% of Prader Willi syndrome cases are due to what?

A

maternal uniparental disomy (two maternally imprinted genes are recieved; no paternal genes received)

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22
Q

What is Angelman syndrome?

A

paternal imprinting disease when the gene from dad is normally silent and the maternal gene is deleted/mutated resulting in:

inappropriate laughter (“happy puppet”)

seizures

ataxia

and severe intellectual disability

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23
Q

What inheritance pattern is shown below?

A

AD- often due to defects in structural genes; often pleiotropic (multiple apparently unrelated effects) and variably expressed

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24
Q

AR recessive pattern

A

Often due to enzymes deficiencies (usually seen in only 1 generation and skips); commonly more severe than dominant disorders and pts often present in childhood

Increased risk in consanguineous families

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25
Q

What inehritance pattern is this?

A

X-linked recessive (sons of heterozygote mothers have a 50% chance of having phenotypic disease); no male to male transmission; skips generations

females must be homozygous to be infected

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26
Q

X-linked dominant pattern

A

Transmitted via both parents; mothers transmit to 50% of sons AND daughters and fathers thansmit to all daughter but no sons

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27
Q

What disease famously has X-linked dominant transmission?

A

Hypophosphatemic rickets (aka vitD resistant rickets)

Results in increased phosphate wasting at the proximal tubules with rickets like presentation

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28
Q

Describe mitochondrial inheritance

A

Transmitted only through the mother and ALL offspring of affected females may show signs of disease

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29
Q

Mitochondrial myopathies often present with what symptoms/signs?

A

myopathy, lactic acidosis, and CNS disase. Secondary to oxidative phosphorylation

muscle biopsy often show ragged red fibers

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30
Q

What are some major AD diseases?

A

ADPKD

Familial adenomatous polyposis

Familial hypercholesterolemia

Hereditary hemorrhagic telangiectasia

Hereditary spherocytosis

Huntington disease

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31
Q

Describe ADPKD

A

Bilateral enlargement of the kidneys due to multiple large cysts that result from mutation of PKD1 (chromosome 16; 16 letters in polycystic kidney) or some in PKD2 (chromosome 4)

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32
Q

Describe familial adenomatous polyposis

A

colon becomes covered with adenomatous polyps after puberty and progresses to colon cancer unless the colon is resected

due to mutation of APC gene on chromosome 5 (5 letters in polyp)

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33
Q

Describe familial hypercholesterolemia and its presentation

A

Elevated LDL due to defective or absent LDL receptor that leads to sever atherosclerotic disease early in life, corneal arcus (below), tendon xanthomas (common on the achilles tendon)

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34
Q

Describe familial hereditary hemorrhagic telangiectasia (aka Osler-Weber-Rendu syndrome) and its presentation

A

Inherited disorder of blood vessles with findings of branching skin lesions (telangiectasias), arteriovenous malformations (AVMs), GI bleeding, and hematuria

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35
Q

Describe hereditary spherocytosis

A

the development of spheroid erthryocytes (below) due to spectrin or ankyrin defects in the RBC membrane

tx with splenectomy

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36
Q

What are the NTM findings of Huntington disease?

A

increased dopamine

decreased GABA and ACh in the brain

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37
Q

What are the findings of Huntington disease?

A

depression, and the onset of chorea progressing to rigid Parkinson like symptoms (caudate atrophy seen)

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38
Q

What causes Huntington disease?

A

CAG trinulceotide repeat on chromosome 4

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39
Q

What are some other AD diseases?

A

Li-Fraumeni syndrome

Marfan syndrome

MEN syndromes (1, 2A, and 2B)

Neuofibromatosis type I (von Recklinghausen disease)

Neurofibromatosis type 2

Tuberous sclerosis

von-Hippel Lindau disease

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40
Q

Describe Li-Fraumeni syndrome

A

abnormalities in TP53 gene cause the occurrence of multiple malignancies at an early age. AKA SBLA cancer syndrome (sarcoma, breast, leukemia, and adrenal gland)

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41
Q

What causes Marfan syndrome?

A

FBN1 mutation on chromosome 15 leading to defective fibrin (scaffold for elastin) which produces a CT disorder affecting skeleton, heart, and eyes.

42
Q

What are the findings of Marfan syndrome?

A

tall with long extremities, pectus ecavatum, hypermobile jointsm and long, tapering fingers and toes (arachnodactyly)

can also cause cystic medial necrosis of the aorta resulting in aortic incompetence and dissecting aneurysms or a floppy mitral valve, as well as subluxation of the lens, typically upward and temporarily

43
Q

What causes MEN1? MEN2A/B?

A

MEN1- MEN1 gene mutation

MEN2A/B- RET gene mutation

44
Q

How does NFM type I present?

A

neurocutaneous disorder characterized by cafe-au-lait spots (below), cutaneous neurofibromas, optic gliomas, pheos, and Lisch nodules (pigmented iris hamartomas)

Note that there is 100% penetrance but very variable expression

45
Q

NFM type 1- cutaneous neurofibromas

A

NFM type 1- optic gliomas

46
Q

NFM type 1- Lisch nodules

A

Lisch nodules

47
Q

What causes NFM type 1?

A

caused by mutation of NF1 gene on chromosome 17 (17 letters in von Recklinghausen)

48
Q

What are the findings of NFM type 2? Cause?

A

bilateral acoustic schwannomas, juvenile cataracts, meningiomas, and ependymomas

NF2 gene on chromosome 22

49
Q

Describe tuberous sclerosis

A

neurocutaneous disorder with multi-organ system involvement, characterized by numerous benign hamartomas (incomplete penetrance, and variable expression)

50
Q

Describe VHL disorder

A

disorder characterized by the development of numerous tumors, both benign and malignant.

Caused by deletion of the VHL gene on chromosome 3 (3 letters)

51
Q

What are some AR diseases?

A

Albinism

ARPKD

cystic fibrosis

glycogen storages diseases

hemochromatosis, Wilson disease

Kartagener syndrome

52
Q

What are some more AR diseases?

A

mucopolysaccharidoses (except Hunter syndrome)

PKU

Sickle cell anemia

sphingolipidoses (except Fabry disease)

thalassemias

53
Q

What causes cystic fibrosis?

A

AR disease caused by a defect in the CFTR gene on chromosome 7 (most commonly a deletion of Phe508)- most common lethal genetic disease in Caucasians

54
Q

What is the pathophysiology of Cystic Fibrosis?

A

CTFR encodes an ATP-gated Cl- channel that secretes Cl- in the lungs and GI tract, and resorbs Cl- in sweat glands. In CF, the protein is misfolded and retained in the RER causing decreased Cl- (and water) secretion.

Increased intracellular chloride results in compensatory Na+ reabsorption via ENaC channels causing increased water reabsorption, which produces abnormally thick mucus secreted into the lungs and GI tract

55
Q

How is Cystic Fibrosis diagnosed?

A

elevated Cl- (60+mEq/mL) in sweat is diagnostic

can present with contraction alkalosis and hypokalemia

elevated immunoreative trypsinogen

56
Q

What are the major complications of Cystic Fibrosis?

A

recurrent pulmonary infections (e.g. Pseudomonas),

chronic bronchitis and bronchiectasis causing a reticulonodular pattern on CXR (below)

pancreatic insufficiency and malabsoprtion with steatorrhea

nasal polyps

57
Q

Other signs of cystic fibrosis?

A

meconium ileus in newborns

bilateral agensis of vas deferens and subfertilty in females (amenorrhea, and thick cervical mucus)

fat soluble (ADEK) vitamin deficiencies

58
Q

How is cystic fibrosis tx?

A

N-acetylcysteine to loosen mucus plugs (cleaves disulfide bonds within mucus glycoproteins)

dornase alfa (DNAse)

59
Q

What are some X-linked recessive disorders?

A

Bruton agammaglobulinemia

Wiskott Aldrich syndrome

Fabry disease

G6PD deficiency

Ocular ablinism

Lesch-Nyhan syndrome

60
Q

What are some more X-linked recessive disorders?

A

Duchenne and Becker muscular dystrophy

Hunter syndrome

Hemophilia A and B

Ornithine transcarbamylase deficiency

61
Q

Mnemonic for X-linked recessive disorders

A

Be Wise, Fool’s GOLD Heeds Silly HOpe

Remember: female carries can be variably affected depending on the percentage inactivation of the X chromosome carrying the mutant vs normal gene

62
Q

What causes Duchenne muscular dystrophy?

A

X-linked disorder typically due to frameshift (deletions, duplications, or nonsense) mutations causing a truncated dystrophin protein that results inhibited muscle regeneration

63
Q

How does Duchenne muscular dystrophy present?

A

onset around 5 yo

weakness starts in the pelvic girdle muscles and progresses superiorly

pseudohypertrophy of the calf muscles due to fibrofatty replacement of muscle (below)

gower manuver (pts use upper extermities to stand up)

waddling gait

64
Q

What is the most common cause of death with Duchenne muscular dystrophy?

A

dilated cardiomyopathy

65
Q

What is dystrophin?

A

the largest protein-coding human gene. Dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle. it connects the intracellular cytoskeleton (actin) to the transmembrane proteins a- and B-dystroglycan, which are conected to the ECM

loss of dystrophin results in myonecrosis

66
Q

How is Duchenne diagnosed?

A

elevated CPK and aldolase are seen

Western blot and muscle biopsy confirm the diagnosis

67
Q

What causes Becker dystrophy?

A

X-linked disorder due to non-frameshift insertions into the dystrophin gene (partially functioning instead of truncated). Thus, similar but less severe than Duchenne (onset is in adolescence or early adulthood)

68
Q

What causes myotonic type I dystrophy?

A

AD disease caused by a CTG trinucleotide repeat expansion in the DMPK gene leading to abnormal expression of myotonin protein kinase

69
Q

How does myotonic type I dystrophy present?

A

myotonia

muscle wasting

cataracts

testicular atrophy

frontal balding

arrhythmias

My tonia, My testicles, My Toupee, and My ticker

70
Q

What causes Fragile X syndrome?

A

X-linked defect affecting the methylation and expression of the FMR1 gene (trinucleotide repeat of CGG) (2nd most common cause of genetic intellectual disability (after Down syndrome))

71
Q

How does Fragile X syndrome present?

A

post-pubertal macroorchisism (enlarged testes)

long face with a large jaw

large everted ears

autism

mitral valve prolapse

72
Q

What are some trinucleotide repeat expansion disorders?

A

Huntington disease

myotonic dystrophy

Friedrich ataxia

Fragile X syndrome

73
Q

Mnemonic for remembering the trinucleotide expansions of these disorders

A

X-Girlfriend’s First Aid Helped Ace My Test

Fragile X: CGG

Friedreich Ataxia: GAA

Huntington: CAG

Myotonic dystrophy: CTG

Remember that these show genetic anticipation (worse disease and earlier age of onset in successive generations)

74
Q

What are the main Autosomal trisomies?

A

Down syndrome (trisomy 21)

Edwards syndrome (trisomy 18)

Patau syndrome (trisomy 13)

75
Q

How does Down syndrome present?

A

intellectual disability

flat facies, prominent epicanthal folds, single palmar crease

gap between 1st 2 toes

duodenal atresia

Hirschsprung disease

congenital heart disease (atrial septal defects ASDs)

Brushfield spots (below)

76
Q

Associations of Down syndrome

A

early-onset Alzheimer disease (chromosome 21 encodes for amyloid precursor proteins)

icnreased risk of ALL and AML

77
Q

95% of Down syndrome cases are due to what:

A

meiotic nondisjunction (associated with advanced maternal age)

4% due to Robertsonian translocation and 1% due mosaicism (post-fertilization mitotic error)

78
Q

Diagnosis of Down syndrome in utero

A

first-trimester ultrasound commonly shows increased nuchal translucency and hypoplastic nasal bone; serum PAPP-A is low and free B-HCG is elevated

2nd trimester quad screen shows decreased a-fetoprotein and inhibin A, and elevated B-HCG and estriol

79
Q

How does Edwards syndrome present?

A

severe intellectual disbaility

rocker-bottom feet

micrognathia (small jaw)

low-set ears

clenched ears with overlapping fingers

prominent occiput

congenital heart disease

80
Q

What is the prognosis for Edwards syndrome?

A

death within 1 yr common

81
Q

What are some serum markers for diagnosing Edwards syndrome?

A

Decreased PAPP-A and free B-hCG in the first trimester

quad screen shows decreased a-fetoprotein, B-hCG, estriol, and inhibin A

82
Q

How does Patau syndrome present?

A

intellectual disability

rocker-bottom feet

micropthalamia (small eyes)

microcephaly

cleft lip/palate

holoprosecenphaly

congenital heart disease (death within 1 yr)

83
Q

How is Patau syndrome diagnosed?

A

first-trimester pregnancy screen shows decreased free B-hCG, decreased PAPP-A, and icnreased nuchal translucency

84
Q
A
85
Q

Mutation of chromosome 3, think:

A

vHL disease and renal cell carcinoma

86
Q

Mutation of chromosome 4, think:

A

ADPKD with PKD2 defect, Huntington disease

87
Q

Mutation of chromosome 5, think:

A

cri-du-chat syndrome, familial adenomatous polyposis

88
Q

Mutation of chromosome 7, think:

A

Williams syndrome, cystic fibrosis

89
Q

Mutation of chromosome 9, think:

A

Friedrich ataxia

90
Q

Mutation of chromosome 11, think:

A

Wilm’s tumor

91
Q

Mutation of chromosome 13, think:

A

Patau syndrome, Wilson disease

92
Q

Mutation of chromosome 15, think:

A

Prader-Willi syndrome, Angelman syndrome

93
Q

Mutation of chromosome 16, think:

A

ADPKD, with PKD1 mutation

94
Q

Mutation of chromosome 18, think:

A

Edwards syndrome

95
Q

Mutation of chromosome 21, think:

A

Down syndrome

96
Q

What is a Robertonian translocation?

A

chromosomal translocation that commonly involves chromosome pairs 13-15, 21, and 22.

Occurs when the long arms of 2 acrocentric chromsomes (chromosomes with centromeres near their ends) fuse at the centromere and the 2 short arms are lost (balanced translocations normally dont cause any abnormaly phenotype, but unbalanced translocations can result in micarriage, stillbirth, and chromosomal imbalances (e.g. Down syndrome, Patau)

97
Q

What is cri-du-chat (aka cry of the cat) syndrome?

A

Congenital microdeletion of the short arm of chromosome 5 producing findings of:

microcephaly

moderate to severe intellectual diability

high-pitched crying/mewing

epicanthal folds

VSDs (heart)

98
Q

What is Williams syndrome?

A

congenital microdeletion of the long arm of chromosome 7 (deleted region includes the elastin gene) resulting in:

distinctive ‘elfin’ facies

intellectual disability

hypercalcemia (sensitivity to vitD)

well-developed verbal skills

extreme friendliness with strangers

CV problems

99
Q

What are the 22q11 deletion syndromes?

A

DiGeorge syndrome and Velocardiofacial syndrome

100
Q

What does microdeletion at 22q11 cause?

A

variable presentations including;

Cleft palate, Abnormal facies,

Thymic aplasia (T cell deficiency)

Cardiac defects

Hypocalcemia secondary to PTH aplasia

CATCH-22

101
Q

What causes 22q11 microdeletion?

A

aberrant development of the 3rd and 4th branchial pouches

102
Q
A

STEP 1 (4) (18 decks)

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