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MOL. BIO LEC > FINAL: MOLECULAR DETECTION OF INHERITED DISEASE > Flashcards

FINAL: MOLECULAR DETECTION OF INHERITED DISEASE 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 MUTATION

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4
Q

more than 2

A

POLYPLOIDY

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5
Q

gain (trisomy) or loss
(monosomy)

A

ANEUPLOIDY

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6
Q

Genome mutations Detection?

A

karyotyping, ploidy
analysis, flow cytometry, & FISH

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7
Q
  • 2 or more genetically distinct populations of cells from 1 zygote in an individual
  • Results from mutation events affecting somatic/germ cells
A

Mosaicism

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8
Q
  • Trisomy 21, 47,XY, + 21
  • 1/700 live births
  • Flat facial profile, mental retardation, cardiac problems, risk of acute leukemia, eventual neuropathological disorders, abnormal immune system
A

Down syndrome

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9
Q
  • Trisomy 18, 47,XY, + 18
  • 1/3,000 live births
  • Severe, clenched fi st; survival less than 1 year
A

Edward syndrome

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10
Q
  • Trisomy 13, 47,XY, + 13
  • 1/5,000 live births
  • Cleft palate, heart damage, mental retardation, survival
    usually less than 6 mo
A

Patau syndrome

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11
Q
  • 47,XXY
  • 1/850 live births
  • Male hypogonadism, long legs, gynecomastia (male breast enlargement), low testosterone level
A

Klinefelter syndrome

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12
Q
  • 47,XYY
  • 1/1,000 live births
  • Excessive height, acne, 1%–2% behavioral disorders
A

XYY syndrome

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13
Q
  • 45,X and variants
  • 1/2,000 live births
  • Bilateral neck webbing, heart disease, failure to develop
    secondary sex characteristics, hypothyroidism
A

Turner syndrome

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14
Q
  • 47,XXX; 48,XXXX
  • 1/1,200 newborn
    females
  • Mental retardation increases with increasing X
A

Multi X females

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15
Q
  • abnormalities in structure
  • Translocations, inversions, deletions,
    duplications, marker chromosomes,
    derivative chromosomes
A

Chromosomal mutations

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16
Q

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

A

Chromosome breakage

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17
Q

is a genetically heterogeneous recessive disorder characterized by defective DNA repair

A

Fanconi anemia

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18
Q
  • rare genetic disorder characterized by growth retardation, sun sensitive skin lesions, and an increased risk of cancer
A

BLOOM SYNDROME

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19
Q
  • rare genetic disorder characterized by progressive neurological dysfunction, immune deficiencies and increase risk of cancer (like lymphoma and leukemia)
A

ataxia
telangiectasia

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20
Q

DETECTION OF CHROMOSOMAL ABNORMALITIES

A

karyotyping, FISH,
microarray technology (CGH)

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21
Q

Examples of Chromosomal Mutations
- del(22q)
- 1/4,000 live births
- CATCH 22 (cardiac abnormality/abnormal facies, T-cell deficit, cleft palate, hypercalcemia)

A

DiGeorge syndrome and
velocardiofacial syndrome

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22
Q
  • del(5p)
  • 1/20,000–1/50,000
    live births
  • Growth deficiency, catlike cry in infancy, small head, mental retardation
A

Cri du chat syndrome

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23
Q
  • del(11p
  • 1/15,000 live births
  • 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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24
Q

affect structural proteins, cell surface receptor proteins, growth regulators, and enzymes

A

Single-gene diseases

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25
Q

DOMINANCE RELATIONSHIPS
- Heterozygous phenotype (child = Tt)
- Homozygous phenotype (1 parent =
TT) Example: height

A

Complete dominance

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26
Q

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

A

Partial/incomplete dominance

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27
Q

DOMINANCE RELATIONSHIPS
- Simultaneously demonstrate the
phenotype of both parents
- Example: ABO blood group

A

Codominance

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28
Q
  • A.K.A. transmission patterns/mode of inheritance
  • 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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29
Q

diagram of family
phenotype/genotype

A

Pedigree:

30
Q

3 main patterns:

A
  • autosomal dominant
  • autosomal recessive
  • sex-linked (X-linked)
31
Q
  • Criteria:
    a. Males and females can be affected. Male-to-male transmission may occur.
    b. Males and females transmit the trait with equal frequency.
    c. Successive generations are
    affected.
    d. 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

32
Q
  • Criteria:
    a. Males and females can be
    affected.
    b. Affected males and females can
    transmit the gene, unless it
    causes death before reproductive
    age
    c. The trait can skip generations.
    d. Parents of an affected individual
    are heterozygous or have the
    traits
  • Affected individuals =homozygous
    recessive genotypes
  • Carriers heterozygotes/asymptomatic
A

Autosomal Recessive Transmission

33
Q
  • Common
  • Always expressed in males
    o inherit the trait from heterozygote/homozygote mother
  • Females are carriers and can only be expressed if the causative allele is
    present in 2 copies
    o inherit the trait from affected father and affected heterozygote mother
  • Ichthyosis, color blindness, hemophilia
A

X-linked recessive transmission:

34
Q
  • Rare
  • Always expressed in females
    o Passed from male to all daughters
    M but to no sons
  • Expressed also in males, with more
    severe effects
  • Rickets, Rett syndrome, incontinentia pigmenti, congenital hypertrichosis
A

X-linked dominant transmission

35
Q

X-linked recessive diseases are carried
by females but manifested most often in _______.

A

MALES

36
Q
  • Freq. of expression of disease phenotype in individuals with a gene lesion
A

Penetrance

37
Q

homozygous recessive

INCOMPLETE OR COMPLETE PENETRANCE?

A

COMPLETE PENETRANCE

38
Q
  • Range of phenotypes in individuals with the same gene lesion
A

Variable Expressivity

39
Q

Molecular Basis of Single-Gene Diseases:
- Molecular methods,
morphological studies, clinical chemistry

A

Detection

40
Q

Molecular Basis of Single-Gene Diseases:
- physiological, morphological and laboratory results

A

Final Diagnosis

41
Q
  • Cause: incompletely digested
    macromolecules due to loss of enzymatic degradation (acid hydrolases)
  • Defects in proteins required for normal
    lysosomal function
    → physical abnormalities
  • Molecular testing: genes that code for the enzymes & their subunits
A

LYSOSOMAL STORAGE DISEASE

42
Q

LYSOSOMAL STORAGE DISEASE
SCREENING?

A

GENE PRODUCT TESTING

43
Q

LYSOSOMAL STORAGE DISEASE
DETECTION OF MUTATION?

A

DIRECT SEQUENCING

44
Q

Substrate Accumulated:
Sphingolipids

DISEASE?

A

Tay–Sachs disease

45
Q

DISEASE:
Von Gierke, McArdle, and Pompe disease

SUBSTRATE ACCUMULATED?

A

Glycogen

46
Q

DISEASE:
Hurler, Sheie (MPS I), Hunter (MPS II), Sanfi lippo (MPS III), Morquio (MPS IV), Maroteaux–
Lamy (MPS VI), Sly (MPS VII)

SUBSTRATE ACCUMULATED?

A

Mucopolysaccharides

47
Q

DISEASE:
Pseudo-Hurler polydystrophy

SUBSTRATE ACCUMULATED?

A

Mucolipids

48
Q

DISEASE:
Niemann–Pick disease

SUBSTRATE ACCUMULATED?

A

Sulfatides

49
Q

Substrate Accumulated:
Glucocerebrosides

DISEASE?

A

Gaucher disease

50
Q

Cause: Single point mutation in the coagulation factor V gene F5 (1q23) at exon 10 (GA at nucleotide 1691,R506Q)
- Genotype: heterozygous form (4%-
8% of the general population) & homozygous (0.06%-0.25%)
- Molecular methods: PCR-RFLP, SSP-PCR
- Other methods: Invader technology,
clot- based methods, family history

A

FACTOR V LEIDEN

51
Q

FACTOR V LEIDEN
inherited blood
clotting disorder

A

Thrombophilia

52
Q

Treatment for blood clot/deep venous
thrombosis?

A

anticoagulants

53
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 PCR - RFLP
  • Phenotypic methods: thrombin time, prothrombin time, platelet count, CBC
    Other: sequencing of factors XI & XIII
A

PROTHROMBIN

54
Q

measure changes in light transmittance during clot formation generating a curve

A

Automated systems

55
Q

METHYLENETETRAHYDROFOLATE REDUCTASE

  • autosomal recessive disorder caused by deficiency of the 5,10-
    methylenetetrahydrofolate reductase (MTHFR) gene product
    o Increased homocysteine levels → predisposition to venous & arterial thrombosis
A

Hyperhomocysteinemia

56
Q
  • Autosomal recessive condition, over absorption 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 HLA-
    H gene product (C282Y, H63D, S65C)
  • Indications for mutation testing:
    clinical symptoms & increased serum
    ferritin & transferrin-iron saturation
  • C282Y mutation detection: PCR-RFLP
A

HEMOCHROMATOSIS

57
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)
  • 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

58
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:
    o 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

59
Q

CONDITIONS THAT DO NOT FOLLOW
MENDELIAN RULES OF INHERITANCE:

A

a. Mitochondrial gene mutations
b. Genomic imprinting
c. Gonadal mosaicism
d. Nucleotide-repeat expansion disorders
e. Multifactorial inheritance

60
Q
  • Maternally inherited
  • mtDNA
    o Circular, 16,569 bp, with 37 genes, 1000-nt control region
  • Mutations affect energy production → muscles & nervous system
  • Molecular methods:
    o Large deletions: Southern blot
    o Point mutations: PCR-RFLP
A

MITOCHONDRIAL (mt) GENE
MUTATIONS

61
Q

mutated mt & normal
mt in the same cell

A

Heteroplasmy

62
Q

Genes that control mitochondrial
functions are found in

A

nuclear genome

63
Q
  • Only 1 copy of a gene in an individual (either from mother or father) is expressed, while the other copy is suppressed
    o 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)
A

GENOMIC IMPRINTING

64
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

65
Q
  • Nucleotide repeats, such as STRS (1-10 bp repeating units) can expand in length during DNA replication & meiosis
A

NUCLEOTIDE-REPEAT EXPANSION DISORDER

66
Q
  • expansions of STR w/3-bp repeating units in the
    gene sequence
    o Fragile X syndrome
    o Huntington disease
    o Idiopathic congenital central hypoventilation syndrome (CCHS)
A

Triplet-repeat mutations

67
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:
    o Karyotyping
    o PCR
    o Southern blot
    o Capillary electrophoresis
A

Fragile X Syndrome

68
Q
  • CAG expansion (9-37 repeats to 38-86 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:
    o Standard PCR methods
    o Capillary electrophoresis
A

Huntington Disease

69
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)

70
Q
  • Disorders (& normal conditions) controlled by multiple genetic &
    environmental factors
    (nutritional/chemical exposures)
  • Phenotypes: conditioned by the no. of controlling genes inherited
  • Detection:
    o HR-array methods
    o NGS
  • Interpretation:
    o Databases (ClinVar & dbSNP)
  • Prognostic & diagnostic value of gene mutation analysis:
    o Annotation of demographics (ethnicity/gender, lifestyles)
A

MULTIFACTORIAL INHERITANCE

MOL. BIO LEC (15 decks)

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