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Hannah MOD > chapter 5: genetic disorders > Flashcards

chapter 5: genetic disorders Flashcards

1
Q

define pleiotropism

A

single mutant gene with many end effects

*characteristic of mendelian disorder

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2
Q

ectopia lentis seen in what disorder

A

marfans

(fibrinillin -1 defect on FBN1 15q21.1

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3
Q

disorders of struncture function or quantity alteration of non-enzyme proteins in mendelian disorders

A

sickle cell (globin molecule structure)
thalassemias (globin molecule amount )
collagen, spectrin, dystrophin, hereditary spherocytosis, osteogenesis imperfects, muscular dystrophies

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4
Q

gene name and location causing cystic fibrosis mutation

A

CFTR gene on chromosome 7q31.2

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5
Q

explain uniparental disomy

A

inheritance of both active chromosomes of a pair from one parent leading to no functional set from the opposite parent
*seen in genomic imprinting disease (Anglemans and Prader Wilili)

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6
Q

proclivity for trinucleotide repeats to expand strongly depends on

A

sex of transmitting parent
(fragile X happens in oogenesis -mom)
(huntington’s happens in spermatogenesis -dad)

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7
Q

incidenece, karyotypes, and features of trisomy 21

A

incidence:
- 1/700 ; 95% have 47 chromosomes
- associated with older lateral age
- 4% related to robertsonian translocation
- 1% are mosaics

karyotypes: 2 copies chr 21 and 1 copy of 12 ; 21/22 translocation with 1 21/22 and 1 22 chromosome. 12/21 translocation with 1 copy of 12/21 and one 12
features: flat facial profile, epicentral folds, slanted palpebral fissures, hypoplastic ears, brush field iris spots, simian crease, wide gap between first and second toes, clinodactyly, fissured tongue, Low IQ

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8
Q

trinucleotide repeat mutations is particularly associated with what type of disorder

A

neurogenerative

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9
Q

inheritance pattern, gene, chromosome, etiology, pathogenesis, and features associated with Marfans syndrome

A

-AD
-gene: FBN1 (some FBN2) chromosome: 15 q 21.1
-fibrillin - 1 defect
-2 mechanisms: loss of structural support in microfibril rich CT and excessive TGF-B activation
-features:
stretchy skin
tall, long extremities, long fingers and toes
double jointed
dolicocphalic (long-headed), frontal bossing, prominent supraorbital ridges
-pectus excavatum
-ectopia lentes (lens dislocation)

complications: mitral valve prolapse, dilation of ascending aorta, passive dilation of the aortic valve ring and aortic root, aortic arch dissection
* Main COD = aortic dissection

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10
Q

complications of turners syndrome

A
  • congenital heart disease (left sided abnormalities: coarctation of the aorta, bicuspid aortic valve) *COD
  • primary amenorrhea
  • hypothryroidism (autoiummune cause)
  • glucose intolerance, obesity, insulin resistance
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11
Q

what disorder is has X q 27.3 mutation

A

fragile X syndrome

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12
Q

which disorder is characterized by ocular changes, skeletal abnormalities, and cardiovascular lesions (MVP and ascending aorta dilation)

A

marfans

-FBN1 on 15 q 21.1

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13
Q

how genetic analysis can benefit infectious disease treatment

A
  • detect microorganism details for dx
  • indicate microorganism drug resistance
  • determination of tx efficacy
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14
Q

traits of autosomal recessive disorders

A
  • largest category of mendelian disorders
  • trait does not usually affect the parents of the individual but does have affected siblings
  • 1/4 chance of being affected
  • is mutation is low frequency then high chance of incest reproduction
  • relate to inborn errors of metabolism
  • homogenous manifestation
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15
Q

3 types of glycogen storage disease

A
  1. von Gierke disease (type 1)
  2. Mcardle disease (type 5)
  3. pope disease (type 2 )
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16
Q

similarities and difference between fragile X syndrome and fragile X tremor/ataxia

A

both

  • CGG repeats
  • both are defects in non-coding regions of genes

syndrome- loss of protein function by transcriptional silencing **mental retardation

ataxia- toxic gain of function/toxic mRNA accumulation by protein structure alteration from transcriptional dysregulation leading to pre-mutations **INTENTION TREMORS AND CEREBELLAR ATAXIA –> PARKINSONS

  • males are affected neurogenerativly
  • females are affected by premature ovarian failure
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17
Q

germ line vs somatic mutation

A

germ line - can be passed on and give rise to inherited disease

somatic - do not cause heritable disease but are important in the genesis of cancer and some congenital malformations

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18
Q

what are the 3 key mechanisms by which unstable trinucleotide repeats cause disease

A
  1. loss of function (transcription silencing by amplifying non-coding regions)
  2. toxic gain of function (expansion in coding region)
  3. toxic gain of function mediated by mRNA (affects non-coding region of gene)
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19
Q

molecular mechanisms associated with genomic imprinting diseases

A
  1. deletions: deletion of imprinted (or silenced) gene leaving only one functional one provided by opposite parent. loss of function from non imprinted gene gives rise to disease
  2. uniparental disomy
  3. defective imprinting: the remaining functional chromosome carries the others imprint therefore no functional alleles present
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20
Q

define mosaicism

A

mitotic error in early development gives rise to two or more populations of cells with different chromosomes in the same individual
*common to affect sex chromosomes

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21
Q

situations that may require cytogenic analysis for inherited genetic alterations of new borns for abnormalities via blood smear

A
  1. multiple congenial abnormalities
  2. metabolic syndrome suspicion
  3. unexplained mental retardation
  4. suspected aneuploidy
  5. suspected monogenic disease (single gene disorder)
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22
Q

gain of function disorders are almost always what inheritance

A

autosomal dominant
**even though loss of function is more common

GOF- huntington protein toxic to neurons
LOF- familial hypercholestermia

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23
Q

3 general approaches to the treatment of lysosomal storage disease

A
  1. enzyme replacement therapy
  2. substrate reduction therapy
  3. molecular chaperone therapy (more recent based on understanding of molecular basis of enzyme deficiency)
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24
Q

chromosomal anomaly and clinical presentation of Di Georges syndrome

A
  • Chr 22 q 11.2 deletion of q 11.2
  • thymic hypoplasia , T-cell immunodeficiency (recurrent viral and fungal infections) , parathyroid hypoplasia leading to hypocalcemia, cardiac malformation, and mild facial anomaly
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25
Q

findings, inheritance, and gene defect of kyphoscoliosis ED

A
  • AD
  • hypotonia, joint laxity, congenital scoliosis, ocular fragility
  • lysyl droxylase defect
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26
Q

details of fragile X syndrome

A
  • single gene disorder (non-classic inheritance)
  • X-linked recessive disorder
  • tri-nucelotide repeat of CGG
  • mutations of FMR-1 gene
  • leads to loss of function by transcription silencing of FMR protein
  • affected males are mentally retarded
  • only 30-50% female carriers are mentally retarded
  • phenotype: long face, large mandible, large everted ears, LARGE TESTICLES, hyper extensible joints, high-arched palate, mitral valve prolapse, strabismus (crossed eyes)
  • exerts anticipation pattern (worsens with generations)
  • premutations from normal transmitting “carrier” male are passed to daughter and are amplified in oogenesis (in mom) and passed to son who will be mentally retarded
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27
Q

new mutations in autosomal dominant disorders seem to occur in germ cells of

A

older fathers

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28
Q

incidence, karyotype, and features of klinefelter syndrome

A
  • 47 XXY (male)
  • 1/660 births
  • male hypogonadism, not dx till puberty
  • are males, with bar body

features: long legs, small atrophic testes, small penis, gynecomastia, low IQ , less body hair, lack of secondary male sex characteristics (deep voice, beard, pubic hair)
complications: infertility (oligospermia), increased risk of T2DM, metabolic syndrome, MVP, osteoporosis, breast cancer

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29
Q

chromosomal anomaly and clinical presentation of velocardofacial syndrome

A

Chr 22 q 11.2 deletion of q 11.2
-facial dysmorphism (prominent pear shaped nose and retrognathia, puffy lids), cleft palate, cardiovascular anomaly, learning disability , short

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30
Q

how is fragile X best diagnosed and why

A

southern blotting
-PCR does not allow for large full mutation dx only normal and premutations (seen in ataxia type)
CGG

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31
Q

3 major consequences of enzyme defects in mendelian disorders and examples

A
  1. accumulation of substrate
    - precursor, intermediate, or alternative product that is toxic
    ex: galactosemia
  2. decreased amount of end product
    ex: albinism (no tyrosinase) Lesch-Nyhan
  3. failure to inactivate a tissue-damaging substrate
    ex: a1- antitrpysin def (cant deactivate neutrophils elastase in lung causing emphysema)
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32
Q

clinical features of trisomy 18 (edwards syndrome)

A
  • rocker-bottom feet
  • micrognathia (small jaw)
  • prominent occiput
  • clenched fists
  • low set eats
  • overlapping fingers
  • renal malformations
  • mental retardation and congenital heart defects
  • early death
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33
Q

effects of mutations in noncoding sequences

A

*do not involve exons
-interfere with binding of transcription factors = reduced/ no transcription
[promoter or enchanter sequence effects]

  • within the intron
  • defective splicing of intervening sequences = pre mRNA processing failure leading inability to form mature mRNA and translation can not occur
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34
Q

findings, inheritance, and gene defect of classic ED

A
  • AD
  • skin/joint hyper mobility, atrophic scars, easy bruising
  • COL5A1/2 defect
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35
Q

enzyme defect, presentation, and morphological findings of Pompe disease

A
  • misc. type of glycogen storage disease
  • lysosomal glucosidase (acid maltase) deficiency
  • morpho changes: mild hepatomegaly, cardiomegaly, skeletal muscle
  • features: CARDIOMEGALY
  • others: muscle hypotonia, cardiorespiratory failure w/i 2 years, early death
  • *adult onset type is more mild with only skeletal muscle involvement (chronic myopathy)
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36
Q

details of huntington’s disroder

A
  • trinucleotide repeat disorder
  • Autosomal dominant disorder
  • CAG repeats
  • HTT gene 4p 16.3
  • gain of function from affect on coding region of gene (exon)
  • repeats occur in spermatogenesis
  • causes polyglutamine expansions with misfolding
  • degeneration of stratal neurons (globus pallidus and caudate nucleus)
  • progressive neuro degeneration , progressive movement disorder, hyperkinetic and jerky, dementia, rigidity
  • anticipation
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37
Q

inheritance, defect, presentation, and morphological findings of Neiman Pick disease type And B

A
  • AR (mainly maternal expression)
  • sulfitiadoses lysosomal storage disease with sphingomyelinase deficiency
  • accumulation of sphingomyelin
  • Chr 11 p 15.4
  • massive splenomegaly
  • 50% have cherry red retinal spot , vacuolation and ballooning of neurons, and brain atrophy
  • Monocyte cells enlarge and look foamy cytoplasms and zebra bodies, blue lipid accumulation in cerebellum

A:

  • missense mutation and NO sphingomylinase
  • severe form
  • extensive neuro defects, hepatosplenomegaly, distended abdomen, marked accumulation, progressive wasting, death by 3 y.o.

B:

  • organomegaly, live to adult hood
  • no CNS defects
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38
Q

inheritance pattern, etiology, pathogenesis, and features associated with familial hypercholesterolemia

A
  • AD “receptor disease”
  • mutation of LDL receptor causing decreased production or abnormal function of LDL receptor (synthesis, transport, binding, clustering, recycling)
  • leads to build up of cholesterol in body
  • homozygotes are more severely affected with 5-6x increase in CHO levels (hetero-2-3x)
  • features: tendinous xanthomas (thickened and yellow extensor tendons) , skin xanthomas, arches cornealis (deposit on rim of cornea), coronary/cerebral/vascular atherosclerosis at early age,
  • *MI before the age of 20
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39
Q

karyotypic abnormalities, clinical features of Turner syndrome

A
  • 45 X
  • hypogonadism in phenotypic females
  • karyotype options:
    1. 45 X0 (complete missing X)
    2. X-chromosome abnormality : partial monosomy of X chromosome (isochromosome of long arm, ring chromosome, deletion of parts of short or long arm
    3. mosaic type: 45 X with 1+ normal or abnormal cell type

features:
- cystic hygroma (infant edema with swelling in neck due to lymph stasis
- bilateral neck webbing (result of hygroma)
- low hairline posteriorly, streak ovaries, peripheral lymphedema, LE low pulse, UE high pulse
- short and fat

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40
Q

what are the different types of point mutations with coding sequences

A

nonsense - codes for a stop codon leading to premature chain termination

missense - changes encodes a different protein leading to different function

silent - changes the code sequence, but codes for the same protein or function

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41
Q

enzyme defect, presentation, and morphological findings of McArdles disease

A
  • myopathic form of glycogen storage disease
  • muscle phosphorylase deficiency
  • morpho changes: skeletal muscle accumulation of glycogen mainly in subsarcolemma
  • features: music cramps after exercise, and failure of lactate levels in blood to rise after exercise bc block of glycolysis
  • others: myoglobinuria, adult onset, elevated serum creatine kinase, normal life span
42
Q

define translocation. and compare the two types

A

translocation: segment of one chromosome is transferred to the other

  1. balanced reciprocal translocation -
    single breaks in each of the two chromosomes with exchange of material
    -no genetic loss, is normal but increased risk of producing abnormal gametes
  2. robertsonian translocation (centric fusion)
    - translocation between 2 acrocentric chromosomes with breaks typically appearing closer to the centromeres of each chromosome
    - leads to one very large chromosome and very small one with deletion of the small one
    - normal phenotype , but produce abnormal progeny
43
Q

benefit of SNP cytogenotyping array

A

-identify single nucleotides polymorphism (SNPS) across genome
-provide genetic marker of transmission
-uncovery copy number abnormalities in pediatric patients with normal karyotype by suspected chromosomal abnormality
(mosacisim, congenital defects, developmental delay like autism)

44
Q

define lyonization and bar body and explain the lyon hypothesis

A
  • inactivation of all but one X chromosome
  • bar body: inactive X seen in interphase nucleus as dark staining mass near nuclear membrane

hypothesis

  • only one X chromosome is active
  • the other undergoes heteropyknosis and is made inactive
  • inactiviatio of which is random in early (day 5) of embryogeneis
  • inactivation of X chromosome persists in all cells from that derivation

*most normal females are mosaics with 2 population of cells (one maternal and paternal X)

45
Q

function of FMR protein [FMRP] and the disease associated

A

fragile X syndrome

  1. selectively binds mRNAs (associated with encoding proteins that regulates synaptic function) to make FMRP-mRNA complex, and regulates their intracellular transport to dendrites
  2. translation regulator - surpresses protein synthesis at synapses therefore no protein suppression causes increases translation and permanent changes in synaptic activity causing mental retardation
46
Q

define aneuploidy ? and causes of it

A

the condition of having an abnormal number of chromosomes in a haploid set.
-resulting in NOT an exact multiple of haploid number (23)

causes:

  1. nondisjunction - gametes have +/- 1 chromosome
  2. anaphase lag - chromatid lags behind in mitosis or meiosis causing one normal cell and one monosomy cell
47
Q

appearance of Neiman pick disease (sulfitadose lysosomal storage disease)

A

foam cell-bubbly appearance (A and B)
or
zebra bodies (C)

48
Q

use of real time PCR

A

monitor frequency of cancer cells via typical blood or tissue lesions

or

infectious load of certain viruses

or point mutation detection in proto-oncogenes

49
Q

situations that may require prenatal cytogenic analysis for inherited genetic alterations of fetuses for abnormalities via aminocentists, chorionic villus biopsy, or umbilical cord blood

A
  1. advnced maternal age
  2. known carrier parent of balanced chromosomal rearrangement
  3. fetal anomalies in ultrasound
  4. routine maternal blood screen showing increased risk of down syndrome
50
Q

benefit of single base primer extension of PCR

A

identifying mutations at specific nucleotide positions

oncogenic mutations are specific sites

51
Q

situations that may require cytogenic analysis for acquired genetic alterations

A
  • dx and management of cancer

- dx and management of infectious disease

52
Q

define mutation

A

permanent change in the DNA

-can be passed on to progeny and gives rise to inherited diseases

53
Q

what disease is periodic acid schiff stain + (PAS +)

A

MPS disorder

54
Q

enzyme defect, presentation, and morphological findings of von gierks disease

A
  • hepatic form of glycogen storage disease
  • Glucose-6-phosphatase deficiency
  • morphological change: hepatomegaly, renomegaly
  • presentation: failure to thrive, stunted growth, hepatomegaly, hypoglycemia, hyperlipidemia, hyperuricemia (gout and xanthomas) , bleeding disorder from platelet dysfunction

*HEPTOMEGALY AND HYPOGLYCEMIA

55
Q

situations that may require cytogenic analysis for inherited genetic alterations of adults for abnormalities

A
  1. inherited cancer syndromes (FH or presentation )
  2. mild monogenic disease
  3. neurogenerative disorder (alzheimers, huningtons)
56
Q

define lysosomal storage dz and its two functional consequences

A

inherited deficiency of lysosomal enzymes that gives rise to 2 consequences:

  1. primary accumulation: no breakdown of enzyme substrate leading to accumulation inside lysosome–> causes lysosome to become large and interfere with normal cell function
  2. secondary accumulation: impaired autophagy and accumulation of autophagic substrates (old mitochondria)–> ROS generation and apoptosis

*cause a lot of tissue damage

57
Q

what disorder is associated with robertsonian translocation

A

trisomy 21
-translocation of q arm of Chr 21 resulting in 46 chromosomes but 3 copies of the long arm of chromosome 21 is being passed on to progeny

46 XY der(15:21) (q10:q10) +21

58
Q

diseases associated with anticipaion

A

huntington’s disease

myotonic dystrophy

59
Q

what is Leber hereditary optic neuropathy

A
  • mitochondrial disease
  • neurogenerative disease that manifests as bilateral loss of central vision starting at ages 15-35 and progression to blindness
  • some cardiac conduction defects may be seen
60
Q

inheritance pattern, etiology, pathogenesis, and features associated with cystic fibrosis (mucoviscidosis)

A
  • autosomal recessive metabolic disorder
  • chloride ion channel defect
  • results in abnormal viscous muscus secretion from goblet cells in all secretory glands including bronchial glands
  • leads to bronchiectasis and emphysema, chronic abscess formation (recurrent superinfection of staphylococcus and pseudomonas) pancreatic insufficiency and male infertility
  • COPD is main cause of death
  • clinical features: malabsorption malnourishment with abdominal distention, bulky foul stool, meconium ileum with no BM at first, failure to thrive, cystic dilation of pancreatic duct, SALTY SKIN
61
Q

characterization of mutations with trinucleotide repeats

A
  • amplification of sequences of 3 nucleotides
  • most commonly C and G repeats
  • leads to anticipation bc amplification is increased during gametogenesis (inherited genetic disorder where subsequent generations are affected earlier with increasing severity)
62
Q

the greater number of X chromosomes in both male and female, the greater the likelihood of ______ developing.
*related to chromosomal disorders

A

mental retardation

63
Q

inheritance, defect, presentation, and morphological findings of Niemann Pick Diz type C

A
  • more common than A or B
  • NPC1 mutation
  • defect of enzymatic lipid transport involved in transport of free cholesterol from lysosome to cytoloplasm
  • accumulation of cholesterol and gangliosides in nervous system
  • sx: progressive neurological damage; ataxia, gaze palsy, dystonia, dysarthria, psychomotor regression
  • Monocyte cells enlarge and look foamy cytoplasms and zebra bodies
64
Q

chr 22 q 11. 2 deletion syndromes

A

di georges syndrome
velocardiofacial syndrome

  • feature: congenital heart defects, palate abnormality, hypocalcemia, variable T-cell immunity
  • cleft lip/palate and abnormal ear folding

CATCH 22

  • cardaic abnormality
  • abnormal facies
  • thymic aplasia
  • cleft palate
  • hypocalcemia/hypoparathyroidism
65
Q

disorders of mutations of single genes that do not follow mendelian pattern (non classic pattern of inheritance)

A
  1. disorders from tri-nucleotide repeats
  2. mitochondrial DNA disorders
  3. genomic imprinting disorders
  4. gonadal mosaicism disorders
66
Q

use of FISH

A
  • fluroscense in Situ hybridization
  • recognize via probes sequences specific to particular chromosomal regions to detect complex translocations or chromosome defects (aneuploidy) \
  • cant be seen with karyotyping or gene amplification
  • need formafilin fixed paraffin embedded tissue
67
Q

what are the different types of lysosomal storage disease and examples of them

A
  1. sphingolipidoses (ganglioside accumulation)
    ex: Tay-Sachs disease
  2. sulfatidoses (sulfatide, sphingomyelin, glucocerebroside accumulation)
    ex: Guacher disease, Niemann Pick Disease (A/B)
  3. mucopolysaccharidoses (MPSs) [mucopolysacchkirises and glycolipid accumulation}
    ex: Hunter and Hurlers
  4. glycogenosis (glycogen accumulation )
    ex: pompe disease
  5. mucolipidoses
68
Q

how genetic analysis can benefit cancer treatment

A
  • detect tumor-specific acquired mutations that are hallmarks of tumors
  • determine clonality (genetic) as indicator of neoplastic condition
  • gene alterations that can affect tx choices
  • determine tx efficacy
  • detection of drug resistant secondary mutations in tailored treated malignancy
69
Q

autosomal dominant vs recessove traits

A

autorecessive

  • defects tend to be more uniform
  • complete penetrance is more common
  • onset is early in life
  • new mutations are rare
  • many mutations involve enzymes (inborn errors of metabolism) leading to decreased amount of normal enzyme or defective enzyme

***autodominant = structural protein loss, or loss of metabolic pathway regulators (like receptors) subject to negative feedback

70
Q

define chromosomal deletion

A

loss of portion of a chromosome

71
Q

inheritance pattern, enzyme defect, clinical presentation, history pattern, and morphologic findings of tay sachs disease

A
  • AR lysosomal storage (sphinogolipidoses)
  • Gm2 gangliosidosis: hexominidase a deficiency
  • build up of gm2 gangliosides in neurons, retina, heart, liver, spleen.
  • HEXA gene. Chr 15
  • presentation: NL at birth, 6 months mental deterioration (motor incoordination, muscular flaccidity, blindness, dementia), cherry red macula
  • by age 1-2 vegetative state, death by age 2-3
  • histo pattern: onion skin whorled lysosomal membranes
  • morpho changes: fat stain oil red O and sudan black B positive
72
Q

define ring chromosome

A

Type of chromosomal deletion:
chromosomal break occurs at both ends of a chromosome with a fusion of the damaged end
(ex. 46 XY r(14) )
-can lose signifanct genetic material and result in phenotype abnormalities
-do not function in mitosis or meiosis normally = serious consequences

73
Q

define isochromosome

A

one are of a chromosome is lost, and the remaining arm is duplicated resulting in 2 short arms (p) or 2 longs arms (q) only

74
Q

appearance of Gaucher cell (sulfitadoses lysosomal storage disease)

A

crumbled tissue paper and large gaucher cells

75
Q

complications of trisomy 21

A

40% get congenital heart disease
-ostium primum, ASD, VSD, and AV valve malformation

10-20x increase of developing acute leukemia by age 20

alzheimers sx after age 40

abnormal immune function with increased risk of lung infection and thyroid autoimmunity

76
Q

clinical features of trisomy 13 (Patau syndrome)

A
  • rocker-bottom feet
  • cleft-lip / palate
  • microopthalmia (small eyes)
  • renal defects
  • cardiac defects
  • mental retardation , holoprosencephlay
  • umbilical hernia
  • cyclops, gastroschisis
  • early death

midline defects

77
Q

prader willi vs anglemans

A
  • genomic imprinting disorder
  • affect Chr 15
  • father carries active prader will gene
  • mother carrier active anglemans gene

praderwilli
-deletion of q 12
-deletion in paternal chromosome with active prader will gene, left with mothers imprinted prader will gene
-del(15) (q 11.2 q 13)
-mental retardation, short stature, hypotonia, profound hyperpagia, obesity, small hands, feet, hypogonadism
(short fat male mentally retarded, no balls)

anglemans

  • deletion of mothers active anglemans gene, left with fathers inactive gene
  • gene UBE3A 15q12
  • ubiquitin ligase defect
  • mental retardation, ataxic jerky gait seizures, innappropriate laughter
  • happy puppets
78
Q

disorders with defects in receptors or transport systems

A

familial hypercholesterolemia (LDL receptor dysfxn)

cystic fibrosis (chloride channel dysfunction)

79
Q

3 broad categories of human genetic disorders and there corresponding penetrance

A
  1. mutation disorders in single genes with large effects
    -aka Mendelian disorders
    -highly penetrant ; rare
    ex: sickle cell anemia
    (effect proteins, receptor proteins, enzymes)
  2. chromosomal disorders (uncommon)
    -high penetrance
    (structural or numerical alterations in autosomes and sex chromosomes)
  3. complex multigenic disorders; multifactorial disorders (most common)
    -aka polymorphisms
    -low penetrance
    (each variant gene confers a small increase dx risk; no single gene necessary to produce dx)
    (ex: heart disease, diabetes, HTN, autoimmune disease, height, weight)
80
Q

traits of autosomal dominant disorders

A
  • incomplete penetrance possible
  • variable expressivity possible
  • age of onset is delayed
  • manifested in heterozygous state
  • at least one parent affected but siblings have equal chance of be affected
  • if no parent is affected then it is cause of new mutation (does not increase risk of sibling development of disorder)
  • many new mutations from older fathers
  • more are loss of function mutations vs gain of function
  • loss of function categories (loss of metabolic regulators, loss of structural proteins)
81
Q

findings, inheritance, and gene defect of vascular ED

A
  • AR
  • thin skin, arterial, or uterine rupture, bruising, small joint hyper extensibility
  • COL3A1 defect
82
Q

4 main categorical defects associated with mendelian disorders

A
  1. enzyme defects
  2. membrane receptor and transport defects
  3. alterations in structure, function, or quantity of non-enzyme products (WIDESPREAD AFFECTS)
  4. mutations resulting in unusual reactions to drugs
83
Q

inheritance pattern, etiology, pathogenesis, and features associated with glucose - 6 - phosphate dehydrogenase deficiency (G6PD)

A
  • X-linked recessive
  • G6PD deficiency
  • *ADVERSE REACTION TO DRUG DISORDER
  • causes drug induced hemolytic reactions
  • antimalarial primaquine –> severe hemolytic anemia
84
Q

inheritance pattern, etiology, pathogenesis, and features associated with ehlers danlos and 3 important types with common features

A
  • 6 types; both AR and AD
  • fibrillar collagen defect
  • feature: gapping defects from fragile skin and joint laxity seen in all

Vascular ED (type 4 ) AD

  • colon rupture
  • large artery rupture
kyphoscoliosis ED (type 6)  AR
-ocular fragliity = cornea rupture, retinal detachment, blindness 
classic ED (type 1 and 2) AD
-diaphragmatic hernia
85
Q

T/F
research shows that even heterozygotes for cystic fibrosis have higher incidence of respiratory and pancreatic diseases as compared with general population

A

true

86
Q

traits of x -linked disorders

A
  • most are recessive
  • affected male does not transmit to son, but all daughters are carriers
  • heterozygous females usually do not express full phenotypic change
  • few dominant ones
  • *vitamin D-resistant rickets
87
Q

what are the transcription factors associated with noncoding sequence mutations

A

MYC
JUN
p53

88
Q

similarities between neimann pick disease and MPS defects

A
  • balloon cells, multiple vacuoles,
  • lamellated zebra bodies

Different bc MPS includes cardiovascular problems

89
Q

benefit of southern blot test

A

detect changes in the structure of specific loci

*good for detection of large tri nucleotide repeats

90
Q

inheritance, defect, presentation, and morphological findings of Gaucher Dz

A
  • AR sulfitdoses lysosomal storage disease
  • mutation of glucocerbrosidase
  • accumulation of glucocerbroside in phagocytes and some CNS
  • leads to activation go MO–>IL-1, TNF, IL-6 release
  • 3 substypes
    1. (chronic) - No CNS defect, skeletal and spleen defects, slight decrease in lifespan (JEW)
    2. (acute neuropathic) - infantile cerebral pattern, CNS defect, early death, hepatosplenomegaly,
    3. (intermediate) systemic involvement with progressive CNS defect that begins in early adulthood

morphological: distended phagocytic cells (Gaucher cells) in liver, spleen, bone marrow, LNs, that looks like crumbled tissue paper
- leads to bone erosion and dysfunction and thrombocytopenia/ pantocytopenia , splenomegaly

tx: stem cell replacement, enzyme replacement

91
Q

define heteroplasty and how it associates with mitochondrial disease

A
  • harboring of tissues of both wild-type (normal) and mutant mitochondrial DNA
  • a minimum number of mutant mtDNA must be present before ox phos dysfxn gives rise to disease “threshold effect”
92
Q

inheritance pattern, etiology, pathogenesis, and features associated with PKU

A
  • autosommal eccessive metabolic disorder
  • phenylalanine hydroxylase (PAH) deficiency
  • no conversion of phenylalanine to tyrosine
  • features: light skin/hair/eyes (bc no melanin from tyrosine), mental retardation, musty odor in urine (diaper) and sweat
  • tx: dietary restriction
93
Q

G-6-P def vs G6PD deficiency

A

G6P def = Von gierke glycogen storage disorder
*large liver

G6PD def = -X-linked recessive

  • *ADVERSE REACTION TO DRUG DISORDER
  • antimalarial primaquine –> severe hemolytic anemia
94
Q

de novo genetic mutation

A

A genetic alteration that is present for the first time in one family member as a result of a mutation in a germ cell of one of the parents, or a mutation that arises in the fertilized egg itself during early embryogenesis.

*Also called de novo variant, new mutation, and new variant.

95
Q

common multifactorial inheritance disorders

A

cleft lip
cleft palate
neural tube defect

96
Q

2 effects on protein encoding associated with deletions and insertions

A
  1. if base pair is multiple of 3 then the reading frame remains intact and causes abnormal protein formation
  2. not multiple of 3 means an altered reading frame and causes a frameshift mutation
97
Q

enzyme defect, presentation, and types of MPS (mucopolysaccharidoses) disease

A
  • AR (Hurler) and X-linked recessive (Hunter)
  • defective glycosaminoglycan (mucopolysaccharide) degradation and build up in phagocytes
  • protein that is abundant in ground substance of connective tissue
  • build up of types: dermatan/heparan/keratin/chrondrotin sulfate
  • features: coarse facial features, cornea clouding, joint stiffness, mental retardation, and MPS in urine
  • PAS + (periodi acid schiff stain)
  • COD: MI or cardiac decompensation
  1. Hurler (type 1 ) *most severe
    - a-1-iduronidase def
    - NL at birth, 6 month = hepatosplenomegaly, progressive cardiovascular complications, growth retardation and death by 10
  2. Hunter (type 2) X-linked
    - no corneal clouding
    - milder clinical course with hepatosplenomegaly and umbilical hernia
98
Q

arcus cornealis vs arcus senilis

A

arcus cornealis is a find in HeFH
-partial arc of white rim around cornea seen in young patients with high cholesterol

arcus senilis
white rim around cornea seen in the elderly not necessarily associated with increased cholesterol levels

99
Q

define chromosomal inversion

A

2 breaks within a chromosome with reincorporation of the inverted break back
*usually normal development

paracentric- on one side of centromere
pericentric- around the centromere

100
Q

true hermaphrodite vs pseudohermaphrodite

A

true
-presences of both ovaries and testes

pseudo

  • disagreement between phenotypic and gonadal sex
  • female pseudo: has ovaries, but male external genitalia
  • male pseudo: has testes, but female -type genitalia
  • associated with congenital adrenal hypoplasia therefore patients can have salt-wasting and should be treated with cortisone
101
Q

what is genomic imprinting

A

selective inactivation of maternal or paternal alleles

  • maternal imprinting = silencing of maternal allele
  • paternal imprinting = silencing of paternal allele
  • imprinting occurs in ovum or sperm before fertilization and is stably transmitted to all somatic cells through mitosis
  • type of epigenetic regulation

Hannah MOD (6 decks)

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