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BPS Exam Study > Chapter 5 - Genetic Diseases > Flashcards

Chapter 5 - Genetic Diseases Flashcards

1
Q

What is the most common category of human genetic disorders?

a) Single gene with large effect
b) Chromosomal disorders
c) Complex multigenic disorders

A

Complex multigenetic disorders

  • caused by interactions between multiple variant forms of genes and environmental factors
    egs. include diabetes mellitus, HTN, autoimmune disorders
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2
Q

What is a point mutation?

A

Mutation in which a single base is substituted for a different base.
May result in a
-missense mutation
- may be ‘conservative’ with little change in function
- may be ‘non-conservative’ e.g sick mutation of beta globin chain of Hb -> sickle cell anaemia
- stop codon

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3
Q

What is a frameshift mutation and the typical result?

A

Deletion/insertion mutation
The number of affected coding bases is not a multiple of 3
Typically the result is the incorporation of a variable number of incorrect amino acids followed by truncation from premature stop codon

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4
Q

What are trinucleotide repeat mutations?

A

Amplification of a sequence of 3 nucleotides
Almost always contain a C and a G
Distinguishing feature is that they are dynamic (i.e. the degree of amplification increases during gametogenesis

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5
Q

What is meant by codominance?

A

Both of the alleles of a gene pair contribute to the phenotype
e.g. blood group antigens

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6
Q

What is the term that implies a single gene may lead to multiple end effects?

A

Pleiotropism

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7
Q

What is meant by the term incomplete penetrance?

A

The inherited mutant gene may be inherited while being phenotypically normal.
Expressed as a %
e.g. 50% penetrance implies that 50% of those who carry the gene express the trait.

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8
Q

What is meant by the term variable expressivity?

A

The trait is seen in all individuals carrying the mutant gene but is expressed differently among individuals
e.g. manifestations of neurofibromatosis type 1

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9
Q

What is the largest category of Mendelian disorders?

A

Autosomal recessive (i.e. occur when both alleles at a given gene locus are mutated)

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10
Q

What is the chance that a sibling will be affected by an autosomal recessive condition?

A

1/4

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11
Q

What are 5 distinguishing features of Autosomal recessive conditions compared to Autosomal dominant?

A
  1. Expression tends to be more uniform in AR disorders
  2. Complete penetrance is common
  3. Onset is frequently early in life
  4. New mutations associated with AR disorders are rarely detected clinically
  5. Many of the mutated genes encode enzymes
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12
Q

Which category of Mendelian disorders includes most inborn errors of metabolism?

A

Autosomal recessive

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13
Q

What type of Mendelian disorder is G6PD deficiency?

A

X-linked

an enzyme deficiency which predisposes to RBC haemolysis in patients receiving certain drugs

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14
Q

What is the inherited defect in Marfan syndrome?

A

Inherited defect in fibrillin-1 (an extracellular glycoprotein)

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15
Q

What are the roles of fibrillin?

A
  • Fibrillin is the major component of microfilaments found in the ECM
  • Fibrillin-1 controls the bioavailability of TGB-beta (and hence limits inflammation)
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16
Q

What is Ehlers-Danlos syndrome?

A

Defect in collagen synthesis or assembly

  • skin, ligaments and joints frequently involved
  • several variants
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17
Q

Name 6 types of Ehlers-Danlos syndrome

A
  • Classic
  • Hypermobility
  • Vascular
  • Kyphoscoliosis
  • Arthrochalasia
  • Dermatospraxis
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18
Q

What is the most common cause of familial hypercholesterolaemia?

A

Mutation in the gene encoding for the receptor of LDL

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19
Q

What are the 3 types of mutations causing familial hypercholesterolaemia (by impairing hepatic clearance of LDL)?

A
  • Mutations in LDL receptor (-> defective LDL clearance)
  • Mutations in genes encoding Apolipoprotein B (-> reduced binding of LDL to LDL receptors)
  • Activating mutation in proprotein convertase subtilisin/kexin type 9 (PCSK9)
    (–> reduced LDL receptors on the cell surface due to increased degradation)
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20
Q

What are the components of VLDL?

A
  • Cholesterol esters
  • Triglycerides
  • Apolipoproteins on surface: Apo-C; Apo-E and B-100
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21
Q

What changes occur when VLDL is converted to LDL?

A

Reduced content of triglycerides compared to VLDL

and Apo-C is lost

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22
Q

What are the 2 options/destinations for IDL?

A
  1. Taken up by liver by receptor mediated transport and recycling to VLDL (approx 50%) OR
  2. Further metabolic processing that removes remaining triglycerides and APO-E –> LDL
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23
Q

Approx what percentage of plasma LDL is cleared by the liver?

A

70%

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24
Q

What is the effect of intracellular cholesterol on: cholesterol synthesis?

A

Suppresses cholesterol synthesis within cells by inhibiting enzyme HMG CoA reductase

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25
Q

What is the effect of intracellular cholesterol on: acyl-coenzyme A?

A

Cholesterol activates the enzyme acyl-coenzyme A -> favours esterification and storage of excess cholesterol

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26
Q

What is the effect of intracellular cholesterol on: LDL receptors

A

Cholesterol suppresses the synthesis of LDL receptors –> protecting cells against excessive accumulation of cholesterol

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27
Q

What is the effect of intracellular cholesterol on: PCSK9

A

Cholesterol upregulates expression of PCSK9 which leads to decreased recycling of LDL receptors

https://www.nps.org.au/australian-prescriber/articles/pcsk9-inhibitors-mechanisms-of-action

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28
Q

How do statins work?

A

Inhibition of HMG CoA reductase -> reduced intracellular cholesterole -> greater synthesis of LDL receptor receptors -> greater uptake of plasma LDL by the cell

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29
Q

Where are lysosomes synthesised?

A

In the endoplasmic reticulum

ad then transported to the Golgi apparatus

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30
Q

What happens to lysosomes in the Golgi apparatus?

A

They undergo a variety of post-translatiomal modifications including attachment of terminal mannose-6-phosphate groups to some of the oligosaccharide side chains

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31
Q

What are 2 pathological consequences that occur from an inherited deficiency of a functional lysosomal enzyme?

A
  1. “Primary accumulation” - accumulation of partially degraded insoluble metabolite within lysosomes (as catabolism remains incomplete)
  2. Defects in autophagy -> Cellular injury
    (autophagy is essential for turnover of mitochondria by a process called mitophagy)
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32
Q

What is the name of the lysosomal storage disease caused by a deficiency of hexosominidase A due to a mutation in the alpha subunit -> inability to catabolise GM2 gangliosides?

A

Tay Sachs Disease

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33
Q

What are the similarities/difference between Niemann-Pick Disease Types A and B?

A

Both are characterised by lysosomal accumulation of sphingomyelin due to an inherited deficiency of sphingomyelinase

  • Type A: missense mutation -> almost complete deficiency of sphingomyelinase. Sever infantile form with extensive neurological involvement.
  • Type B: organomegaly but generally no CNS involvement.
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34
Q

What is the morphology of Niemann-Pick disease (type A/B)?

A

affected cells become enlarged due to distention of lysosomes and sphingomyelin and cholesterol

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35
Q

What is the most common type of Niemann-Pick disease?

A

Type C

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36
Q

What mutations account for most of Niemann-Pick type C disease?

A

NPC1
-> defect in cholesterol transport and accumulation of cholesterol in CNS

Both NPC1 (membrane bound) and NPC2 (soluble) are involved in transport of free cholesterol from lysosomes to the cytoplasm.

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37
Q

What is the most common lysosomal storage disorder?

A

Gaucher disease

- refers to a cluster of AR disorders resulting from mutations in the genes encoding glucocerebrosidase

38
Q

Which enzyme is affected in Gaucher disease?

A

Glucocerebrosidase

- enzyme that normally cleaves glucose residue from ceramide

39
Q

A mutation of which gene is the most common genetic risk factors for the development of Parkinson disease?

A

Glucocerebroside gene

reciprocal relationship between the level of this enzyme and the aggregation of alpha synuclein

40
Q

What are the clinical features of Type 1 Gaucher disease?

A

Type 1 Gaucher disease presents in adult life
Splenomegaly - pancytopenia / thrombocytopenia or
Bone involvement - pathological #s, bone pain

41
Q

What are the clinical features of type II and III Gaucher disease?

A

CNS dysfunction
convulsions
progressive mental deterioration

42
Q

What is the most common mode of inheritance of Mucopolysaccharidoses (MPSs)

A 
autosomal recessive
(all of MPS clinical variants except Hunter syndrome which is X-linked)
43
Q

What are the 3 major subgroups of glycogen storage disease?

A
  1. Hepatic form (liver cells store glycogen due to a lack of hepatic glucose-6-phosphatase)
  2. Myopathic form (lack of muscle phosphorylase -> excess glycogen in skeletal muscles)
  3. Miscellaneous (e.g. Pompe disease - lack of lysosomal acid alpha-glucosidase)
44
Q

What is aneuploidy?

A

When an error occurs in meiosis or mitosis and a cell acquires a chromosome complement that is not an exact multiple of 23
(usual causes are nondisjunction and anaphase lag)

45
Q

What is mosaicism?

A

2 or more populations of cells with different chromosomal complement in the same individual
(affecting sex chromosomes is relatively common. Autosomal much less common)

46
Q

What is the term for a loss of a portion of a chromosome?

A

Deletion
(most are interstitial - loss between 2 breaks.
occasionally are terminal - single break in a chromosome arm
ring chromosome - special form of deletion)

47
Q

What is the term for a rearrangement that involves 2 breaks in single chromosome with reincorporation of the inverted, intervening segment

A

Inversion
(may be paracentric - involving only 1 arm or
pericentric - breaks on opposite sides of centromere)

48
Q

What results when 1 arm of a chromosome is lost and the remaining arm is duplicated

A

Isochromosome

49
Q

What is the term when segment of one chromosome is transferred to another

A

Translocation

50
Q

What is the most common cause of trisomy?

A

Meiotic nondisjunction

51
Q

What are the clinical features of Klinefelter syndrome

A
  • male hypogonadism
  • common cause of male infertility
  • 2 or more X chromosomes; 1 or more Y chromosomes
  • increased incidence of metabolic syndrome
  • increased risk of congenital heart disease particularly mitral valve prolapse
52
Q

What is Turner syndrome?

A

complete/partial monosomy of the X chromosome

charterised by hypogonadism in phenotypic females

53
Q

Name 3 diseases caused by trinucleotide repeat mutations in expansions affecting non-coding regions

A

Fragile X syndrome
Friedreich ataxia
Myotonic dystrophy

54
Q

Name 2 diseases caused by trinucleotide repeat mutations affecting coding regions

A

Huntington disease

Spinocerebellar ataxia

55
Q

What proportion of carrier females are affected (i.e have intellectual disability and other clinical features) in Fragile X syndrome?

A

30-50%

This is higher than in other X-linked disorders

56
Q

What are carrier males of Fragile X syndrome referred to as?

A

Normal transmitting males

because carrier males transmit the trait through all their phenotypically normal daughters to affect grandchildren

57
Q

What determines the presence and severity of clinical symptoms in Fragile X syndrome?

A

The amplification of CGG repeats of the FMRI gene
Patients with Fragile X syndrome have an extremely large expansion of 200-4000 repeats
Normal range of CGG repeats is 6-55
Normal transmitting males and carrier females carry 55-200 CGG repeats

58
Q

Which 2 organs is the FMR protein (product of FMR1 gene) most abundant?

A

Brain and testes

59
Q

What are 2 disorders that CGG premutations in the FMR1 gene can cause that are phenotypically different to Fragile X syndrome and occur through a distinct mechanism involving a toxic gain of function?

A
  • Fragile X-associated tremor/ataxia syndrome

- Fragile X associated primary ovarian failure

60
Q

What is the “threshold effect” in terms of mitochondrial gene mutations

A

A minimum number of mutant DNAs must be present in a tissue before oxidative phosphorylation gives rise to a disease

61
Q

What is the mode of inheritance of Leber hereditary optic neuropathy?

A

Mitochondrial inheritance

62
Q

What is the term for the epigenetic process which involves transcriptional silencing of the paternal or maternal copies of certain genes during gametogenesis?

A

Genomic imprinting

63
Q

What is maternal imprinting?

A

Transcriptional silencing of the maternal allele

64
Q

What is paternal imprinting?

A

Transcriptional silencing of the paternal allele

65
Q

What chromosome is affected in Prader-Willi syndrome?

A

The deletion affects the paternally derived chromosome 15

66
Q

What is the difference in inheritance between Angelman syndrome and Prader-willi syndrome?

A

Prader Willi syndrome - deletion affects the paternally derived chromosome gene region
Angelman syndrome - deletion affects the maternally derived chromosome gene region

67
Q

What are the additional clinical features seen in Angelman syndrome (compared to Prader willi)

A

Microcephaly; ataxic gait; seizures; inappropriate laughter

68
Q

What is the difference between constitutional and somatic genetic markers?

A

Constitutional - present in every cell of affected person

Somatic - restricted to specific tissue types or lesions

69
Q

What is the name of sequencing which involves PCR using primers for many different genomic regions performed simultaneously

A

Next generation sequencing

70
Q

PCR type that is a useful approach for identifying mutations at a specific nucleotide position

A

Single based primer extension

71
Q

PCR that takes advantage of the digestion of DNA with endonucleases known as restriction enzymes that recognise and cut DNA at specific sequences

A

Restriction fragment length analysis

72
Q

Single PCR product mixed with a DNA polymerase, a specific primer, nucleotides and four dead-end nucleotides with different fluorescent tags .
Ensuing reaction -> ladder of DNA molecules labeled with different tags
After size separation by electrophoresis, the sequence is “read” and compared with the normal sequence to detect mutations

A

Sanger sequencing

73
Q

Genotypic array that are routinely used to uncover copy number abnormalities in paediatric patients when the karyotype is normal but a structural chromosomal abnormality is still suspected.
Can identify loss of heterozygosity.
Important in diagnosis of disorders caused by uniparental disomy (e.g. Prader Willi syndorme and Angelman syndrome)

A

Single nucleotide polymorphisms (SNP) genotyping arrays

74
Q

The most useful types of genetic polymorphismsfor linkage analysis

A

SNPs (single nucleotide polymorphisms)

Minisattelite and microsatellite repeats

75
Q

The study of heritable chemical modification of DNA or chromatin that does not alter the protein-encoding DNA sequence itself

A

Epigenetics

76
Q

Molecular analysis technique that uses DNA probes that recognise sequences specific to particular chromosomal regions
Large fragments of clonal genomic DNA spanning up to 200kb and labeled with fluorescent dyes and applied to metaphase chromosome preparations or interphase nuclei that are pre-treated

A

Fluorescence in situ Hybridisation

77
Q

Test DNA and a reference DNA are labeled with 2 different fluorescent dyes
Samples mixed and hybridized to an array spotted with DNA probes that span the human genome at regular intervals
Comparison of binding of labelled DNA from the 2 samples

A

Cytogenomic Array Technology

78
Q

To what category of genetic diseases does Gaucher disease belong? Name some other diseases in this group

A

Lysosomal storage disease

Other examples are Pompe disease, Tay-Sachs disease, and the mucopolysaccharidoses.

79
Q

What are the indications for analysis of inherited genetic alterations in newborns or children? (name 5)

A
  • Multiple congenital anomalies
  • suspicion of a metabolic syndrome
  • unexplained intellectual disability and/or developmental delay
  • suspected aneuploidy
  • suspected monogenic disease
80
Q

Indications for inherited genetic testing in adult patients? (name 3)

A
  • inherited cancer syndromes (family history or an unusual caner presentation)
  • atypically mild monogenic disease (e.g. attenuated cystic fibrosis)
  • neurodegenerative disorders (e.g. Huntingon disease)
81
Q

Indications for analysis of acquired genetic alterations? (name 2 common indications)

A
  • Diagnosis and management of cancer
  • Diagnosis and management of infectious disease e.g determination of treatment efficacy of HIV; identification of genetic alterations in microbes associated with drug resistance
82
Q

Which two types of genetic polymorphisms are most useful for linkage analysis?

A
  • SNPs

- minisatellite/microsatellite repeats

83
Q

Why is DNA-based diagnosis generally preferred to RNA analysis?

A

DNA is much more stable

84
Q

What is a morphological hallmark of trinucleotide repeat disorders of coding regions?

A

Accumulation of aggregated mutant proteins in large intranuclear inclusions

85
Q

What pattern of inheritance accounts for autosomal dominant conditions where phenotypically normal parents have more than one affected child (e.g. osteogenesis imperfecta)?

A

Gonadal mosaicism

86
Q

What is the mode of inheritance of G6PD deficiency?

A

X-linked recessive inheritance

87
Q

What is the most common mode of inheritance of Marfan syndrome?

A

Autosomal dominant

88
Q

What is an ophthalmological sign characteristic of Tay Sachs disease?

A

Cherry red spot in the macular

89
Q

Which organ is most affected in Pompe disease?

A

Heart - cardiomegaly

90
Q

What is Pompe disease?

A

Glycogen storage diseases associated with deficiency of acid alpha-glucosidase

91
Q

What is von Gierke disease?

A

Glycogen storage disease (hepatic type) with deficiency of glucose-6-phosphatase

92
Q

What is McArdle disease?

A

Glycogen storage disease (myopathic type). Deficiency of muscle phosphorylase

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