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MOLECULAR BIOLOGY > FINALS LEC: Molecular Detection of Inherited Diseases > Flashcards

FINALS LEC: Molecular Detection of Inherited Diseases Flashcards

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1
Q

Caused by mutations (changes) in germ cells that are passed down from parent to child

A

Inherited Diseases

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2
Q

Mutations in Somatic Cell

A
  1. Cancer
  2. Congenital malformations (present at birth): due to factors upsetting the developmental process
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3
Q

Abnormal chromosome #

A

Genome Mutations

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4
Q

more than 2 sets

A

Polyploidy

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5
Q

gain (trisomy)/loss (monosomy)

A

Aneuploidy

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6
Q

Detection for genome mutations:

A

karyotyping, ploidy analysis, flow cytometry, & FISH

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7
Q

Flat facial profile, mental retardation, cardiac problems. risk of acute leukemia, eventual neuropathological disorders, abnormal immune system

A

down syndrome

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8
Q

Severe, clenched fist; survival less than 1 year

A

edward syndrome

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9
Q

Cleft palate, heart damage, mental retardation, survival usually less than 6 mo

A

patau syndrome

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10
Q

Male hypogonadism, long legs, gynecomastia (male breast enlargement), low testosterone level

A

klinefelter syndrome

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11
Q

Excessive height, acne, 1%-2% behavioral disorders

A

XYY SYNDROME

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12
Q

Bilateral neck webbing, heart disease, failure to develop secondary sex characteristics, hypothyroidism

A

turner syndrome

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13
Q

Mental retardation increases with increasing X

A

Multi X females

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14
Q

Trisomy 21, 47,XY+21

A

Down syndrome

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15
Q

Trisomy 18, 47,XY+18

A

Edward syndrome

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16
Q

Trisomy 13, 47,XY+13

A

Patau syndrome

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17
Q

47,XXY

A

Klinefelter syndrome

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18
Q

47,XYY

A

XYY SYNDROME

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19
Q

45X and variants

A

turner syndrome

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20
Q

47,XXX: 48,XXXX

A

Multi X females

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21
Q

Abnormalities in chromosome structure

A

Translocations, inversions, deletions, duplications, marker chromosomes, derivative chromosomes

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22
Q

caused by chemicals, radiation, chromosome breakage syndromes (Fanconi anemia, Bloom syndrome, ataxia telangiectasia)

A

Chromosome breakage

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23
Q

Chromosomal mutations detection

A

karyotyping, FISH, microarray technology (CGH)

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24
Q

CATCH 22 (cardiac abnormality/abnormal facies, T-cell deficit, cleft palate, hypercalcemia)

A

DiGeorge syndrome and velocardiofacial syndrome

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25
Q

Growth deficiency, catlike cry in infancy, small head, mental retardation

A

Cri du chat syndrome

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26
Q

Aniridia (absence of iris), hemihypertrophy (one side of the body seems to grow faster than the other), and other congenital anomalies.

A

Contiguous gene syndrome; Wilms tumor, aniridia, genitourinary anomalies, mental retardation syndrome

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27
Q

del(22q)

A

Cri du chat syndromeDiGeorge syndrome and velocardiofacial syndrome

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28
Q

del(5p)

A

Cri du chat syndrome

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29
Q

del (11p)

A

Contiguous gene syndrome; Wilms tumor, aniridia, genitourinary anomalies, mental retardation syndrome

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30
Q

Single-gene diseases affect structural proteins, cell surface receptor proteins, growth regulators, and enzymes

A

Patterns of Inheritance in Single-Gene Diseases

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31
Q

3 Dominance Relationships

A

Complete dominance
Partial/incomplete dominace
Codominance

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32
Q

 Heterozygous phenotype (child=Tt)  Homozygous phenotype (1 parent = TT)
 Example: height

A

Complete dominance

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33
Q

 Offspring phenotype is variably intermediate (combine) between the homozygous & heterozygous parentals
 Example: gene affecting hair texture

A

Partial/incomplete dominance

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34
Q

 Simultaneously demonstrate the phenotype of both parents
 Example: ABO blood group

A

Codominance

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35
Q

Dominant allele will mask the effect of the recessive allele completely

A

Complete Dominance

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36
Q

Both the alleles are dominant

A

Codominance

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37
Q

A.K.A. transmission patterns/mode of inheritance

A

Patterns of Inheritance in Single-Gene Diseases

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38
Q

 The manner in which a genetic trait, disorder, or risk of disorder is passed from one generation to the next
 Determined by examination of family histories

A

Patterns of Inheritance in Single-Gene Diseases

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39
Q

diagram of family phenotype/genotype

A

Pedigree

40
Q

Patterns of Inheritance in Single-Gene Disease 3 main patterns:

A

autosomal dominant, autosomal recessive, sex-linked (Xlinked)

41
Q

 Criteria:
1. Males and females can be affected. Male-to-male transmission may occur.
2. Males and females transmit the trait with equal frequency.
RECESSIVE DOMINANT
3. Successive generations are affected.
4. Transmission stops after a generation in which no one inherits the mutation.
 Affected individual: has dominant allele
 Parent 1 (affected) x Parent (2) (unaffected) = 50%-100% risk/likelihood of expressing the disease phenotype on the child

A

Autosomal Dominant Transmission

42
Q

 Criteria:
1. Males and females can be affected. 2. Affected males and females can transmit the gene, unless it causes death before reproductive age.
3. The trait can skip generations. 4. Parents of an affected individual are heterozygous or have the traits
 Affected individual: homozygous recessive genotypes
 Carriers: heterozygotes/ asymptomatic

A

Autosomal Recessive Transmission

43
Q

Sex-Linked Transmission

A

X-linked recessive transmission
X-linked dominant transmission

44
Q

 Common
 Always expressed in males
 Inherit the trait from heterozygote/homozygote mother
 Females are carriers and can only be expressed if the causative allele is present in 2 copies
 Inherit the trait from affected father & affected heterozygote mother
 Ichthyosis, colorblindness, hemophilia

A

X-linked recessive transmission

45
Q

 Rare
 Always expressed in females
 Passed from male to all daughters but to no sons
 Expressed also in males, with more severe effects
 Rickets, Rett syndrome, incontinentia pigmenti, congenital hypertrichosis

A

X-linked dominant transmission

46
Q

Freq. of expression of disease phenotype in individuals with a gene lesion

A

Penetrance

47
Q

homozygous recessive

A

Complete penetrance

48
Q

 Range of phenotypes in individuals with the same gene lesion
 Example: polydactyly

A

Variable expressivity

49
Q

Detection: Molecular methods, morphological studies, clinical chemistry Final diagnosis: physiological, morphological, & laboratory results

A

Single-Gene Disorders

50
Q

 Cause: incompletely digested macromolecules due to loss of enzymatic degradation (acid hydrolases)
 Defects in proteins required for normal lysosomal function  physical abnormalities
 Screening: gene product testing  Molecular testing: genes that code for the enzymes & their subunits
 Detection of mutation: direct sequencing

A

Lysosomal Storage Disease

51
Q

 Cause: Single point mutation in the coagulation factor V gene F5 (1q23) at exon 10 (1691G>A, R506Q)
 Genotype: heterozygous form (4%8% of the general population) & homozygous (0.06%-0.25%)
 Thrombophilia: inherited blood clotting disorder
 Treatment for blood clot/deep venous thrombosis: anticoagulants
 Molecular methods: PCR-RFLP, SSP-PCR
 Other methods: Invader technology, clot-based methods, family history

A

Factor V Leiden

52
Q

 Precursor to thrombin in the coagulation cascade
 Autosomal-dominant increased risk of thrombosis: mutation in the 3’ untranslated region of the gene that codes for prothrombin or coagulation factor II, F2 (11p11-q12)x
 Laboratory tests: F2 & F5 mutations  Molecular methods: multiplex PCRRFLP
 Phenotypic methods: thrombin time, prothrombin time, platelet count, CBC
 Automated systems: measure changes in light transmittance during clot formation generating a curve
 Other: sequencing of factors XI & XIII

A

Prothrombin

53
Q

autosomal recessive disorder caused by deficiency of the 5,10methylenetetrahydrofolate reductase (MTHFR) gene product

A

Hyperhomocysteinemia

54
Q

 Genetic alterations: 677C>T
(p.A222V) & 1298A>C (p.E429A)  deficiencies in folate metabolism
 Detection: standard/multiplex PCR with RFLP (HinfI & MboII) or sequencing, multiplex qPCR, HR-MCA

A

Methylenetetrahydrofolate Reductase

55
Q

 Autosomal recessive condition, overabsorption of iron from food  pancreas, liver, & skin damage; heart disease; diabetes
 Diagnosis: measurement of blood iron levels, transferrin saturation, liver biopsy
 Molecular cause: dysfunction of the hemochromatosis type I HFE or HLAH gene product (C282Y, H63D, S65C)
 Indications for mutation testing: clinical symptoms & increased serum ferritin & transferrin-iron saturation
 C282Y mutation detection: PCRRFLP

A

Hemochromatosis

56
Q

 Life-threatening autosomal recessive disorder that causes severe lung damage & nutritional deficiencies
 Affects cells that produces mucus, sweat, saliva, & digestive juices  secretions become thick & sticky
 Cause: loss of function of the CFTR gene (3-bp deletion F508del & 1,900 other mutations such as G542X, G551D, N1301K, R117H, W1282X, 1717-1G>A) (Human Genome Variation Society www.genet.sickkids.on.ca)
 Molecular tests for mutation detection: RFLP, PCR-RFLP, HA, temporal-gradient gel electrophoresis, SSCP, SSP-PCR, cleavase, bead array technology, & direct sequencing

A

Cystic Fibrosis

57
Q

 Group of mono-oxygenase enzymes localized to the ER
 Present in high concentrations in the liver & small intestine  enzymes metabolize & detoxify compounds (drugs)
 Polymorphisms affect the metabolism of hormones, caffeine, chemotherapeutic drugs, antidepressants, & oral contraceptives:  Tests are used to predict the response to drugs
 Detection of polymorphisms: allele -specific PCR
 Screening tests: microarray, bead array, sequencing

A

Cytochrome P-450

58
Q

Do not follow Mendelian rules of inheritance:

A

 Mitochondrial gene mutations
 Genomic imprinting
 Gonadal mosaicism
 Nucleotide-repeat expansion disorders
 Multifactorial inheritance

59
Q

 Maternally inherited
 mtDNA
 Circular, 16,569 bp, with 37 genes, 1000-nt control region
 Database of mt genes & mutations:
http://www.MITOMAP.org
 Mutations affect energy production  muscles & nervous system
 Heteroplasmy: mutated mt & normal mt in the same cell
 Molecular methods:
 Large deletions: Southern blot
 Point mutations: PCR-RFLP

A

Mitochondrial (mt) Gene Mutations

60
Q

 Only 1 copy of a gene in an individual (either from mother or father) is expressed, while the other copy is suppressed
 Example: mules (male donkey x female horse) & hinnies (male horse x female donkey)
 Cause: transcriptionally silencing through histone/DNA modification
 Genetic disorders: 1 or other allele of a gene is lost (uniparental disomy)
 Examples:
1. Prader-Willi syndrome: paternal del(15)(q11q13)
2. Angelman syndrome: same region, maternal

A

Genomic Imprinting

61
Q

Cytogenetic methods:

A

 Translocations & some deletions: standard karyotyping
 Microdeletions: HR-karyotyping
 FISH with labeled probes

62
Q

Molecular methods:

A

 PCR-RFLP/STR analysis
 Methylation-specific PCR
 Southern blot using methylation-specific restriction enzymes
 Assays developed for CNV detection: FISH, array-based CGH, NGS

63
Q

 Generation of new mutations in germline cells  giving rise to eggs/sperm carrying the mutation which then becomes a heritable phenotype
 Expected when phenotypically normal parents have more than 1 affected child
 Example: osteogenesis imperfecta

A

Gonadal Mosaicism

64
Q

 Nucleotide repeats, such as STRs (1-10 bp repeating units) can expand in length during DNA replication & meiosis
 Triplet-repeat mutations: expansions of STR w/ 3-bp repeating units in the gene sequences
 Fragile X syndrome
 Huntington disease  Idiopathic congenital central hypoventilation syndrome (CCHS)

A

Nucleotide-Repeat Expansion Disorder

65
Q

 CGG expansion (up to >2,000 repeats) in the noncoding region 5’ to the FMR-1 gene
 Symptoms (increase in severity with each generation): learning disorders & mental retardation (IQ~20), long face, large ears, macroorchidism
 Detection:
 Karyotyping
 PCR
 Southern blot
 Capillary electrophoresis

A

Fragile X Syndrome

66
Q

 CAG expansion (9-37 repeats to 3886 repeats) in the huntingtin structural gene (4p16.3)
 Symptoms: impaired judgment, slurred speech, difficulty in swallowing, chorea, personality changes, depression, mood swings, unsteady gait, intoxicated appearance
 Detection: standard PCR methods, capillary electrophoresis

A

Huntington Disease

67
Q

 Gene mutations in PHOX2b gene in chromosome 4: insertion of multiple alanine residues
 Inadequate breathing while asleep, hypoventilation while awake
 Occurs in association with an intestinal disorder (Hirschsprung disease) & symptoms of ANS
dysregulation/dysfunction
 Detection:  PCR w/ 32P-labeled primer & polyacrylamide gel electrophoresis
 Standard PCR & agarose gel electrophoresis

A

Idiophatic Congenital Central Hypoventilation Syndrome (CCHS)

68
Q

 Disorders (& normal conditions) controlled by multiple genetic & environmental factors (nutritional/chemical exposures)
 Phenotypes: conditioned by the no. of controlling genes inherited
 Detection:  HR-array methods  NGS
 Interpretation:  Databases (ClinVar & dbSNP)
 Prognostic & diagnostic value of gene mutation analysis:  Annotation of demographics (ethnicity/gender, lifestyles)

A

Multifactorial Inheritance

69
Q

 Phenotypic methods: treatment is directed to the phenotype
 Genes with variable expressivity
 Gene mutation may not predict the severity of the phenotype
 Clotting time & transferrin saturation
 Better guides for anticoagulant treatment
 Molecular testing
 May discover genetic lesions in the absence of symptoms
 Offer only a diagnosis, not a cure

A

Limitations of Molecular Testing

70
Q

Lysosomal Storage Disease screening:

A

gene product testing

71
Q

Lysosomal Storage Disease molecular testing:

A

genes that code for the enzymes & their subunits

72
Q

Lysosomal Storage Disease Detection of mutation:

A

direct sequencing

73
Q

inherited blood clotting disorder

A

Thrombophilia

74
Q

Treatment for blood clot/deep venous thrombosis:

A

anticoagulants

75
Q

Molecular methods of Factor V Leiden:

A

PCR-RFLP, SSP-PCR

76
Q

Autosomal-dominant increased risk of thrombosis:

A

mutation in the 3’ untranslated region of the gene that codes for prothrombin or coagulation factor II, F2 (11p11-q12)x

77
Q

Laboratory tests for prothrombin:

A

F2 & F5 mutations

78
Q

Molecular methods of prothrombin:

A

multiplex PCR-RFLP

79
Q

Phenotypic methods of prothrombin:

A

thrombin time, prothrombin time, platelet count, CBC

80
Q

Automated systems of prothrombin:

A

measure changes in light transmittance during clot formation generating a curve

81
Q

Detection of Methylenetetrahydrofolate Reductase:

A

standard/multiplex PCR with RFLP (HinfI & MboII) or sequencing, multiplex qPCR, HR-MCA

82
Q

C282Y mutation detection:

A

PCR-RFLP

83
Q

Molecular tests for mutation detection of cystic fibrosis:

A

RFLP, PCR-RFLP, HA, temporal-gradient gel electrophoresis, SSCP, SSP-PCR, cleavase, bead array technology, & direct sequencing

84
Q

Detection of polymorphisms for Cytochrome P-450:

A

allele -specific PCR

85
Q

Screening tests for Cytochrome P-450:

A

microarray, bead array, sequencing

86
Q

Mutations affect energy production

A

muscles & nervous system

87
Q

Mutations affect energy production

A

muscles & nervous system

88
Q

mutated mt & normal mt in the same cell

A

Heteroplasmy

89
Q

Molecular methods for mitochondrial gene mutations:
 Large deletions:
 Point mutations:

A

Southern blot , PCR-RFLP

90
Q

Cause: transcriptionally silencing through histone/DNA modification

A

Genomic Imprinting

91
Q

Examples:
1. Prader-Willi syndrome: paternal del(15)(q11q13)
2. Angelman syndrome: same region, maternal

A

Genomic Imprinting

92
Q

Expected when phenotypically normal parents have more than 1 affected child

A

Gonadal Mosaicism

93
Q

expansions of STR w/ 3-bp repeating units in the gene sequences

A

Triplet-repeat mutations

94
Q

Symptoms (increase in severity with each generation): learning disorders & mental retardation (IQ~20), long face, large ears, macroorchidism

A

Fragile X Syndrome

95
Q

Symptoms: impaired judgment, slurred speech, difficulty in swallowing, chorea, personality changes, depression, mood swings, unsteady gait, intoxicated appearance

A

Huntington Disease

96
Q

Inadequate breathing while asleep, hypoventilation while awake
 Occurs in association with an intestinal disorder (Hirschsprung disease) & symptoms of ANS
dysregulation/dysfunction

A

Idiophatic Congenital Central Hypoventilation Syndrome (CCHS)

MOLECULAR BIOLOGY (9 decks)

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