Genetics

Question 1

Pathogenesis of Fabry’s Disease?

Answer 1

X linked lysosomal storage disorder. Deficiency of alpha-galactosidase A which leads to accumulation of globotriaosyl ceramide (Gb3) in lysosomes of variety of cells such as cardiac, neural and skin cells. 80% of population will have neurological, dermatological and cardiac manifestations such as hypertrophic cardiomyopathy and angiokeratomas.

Question 2

Pathogenesis of haemochromatosis?

Answer 2

Autosomal recessive.
2 mutations of H FE genes have been described - C282Y/H63D
Prevalence of homozygotes are high but generally lower penetrance of ~30%
The precise mechanism by which mutation of the HFE gene leads to iron overload is not known.

Question 3

How is vWD transmitted?

Answer 3

Type 1 and 2 are AD.

Type 3 is AR.

Question 4

How is alpha 1 antitrypsin deficiency transmitted?

Answer 4

Co-dominant trait.

Question 5

What is the pathogenesis of Duchennes/Beckers myotonic dystrophy?

Answer 5

Defective gene located on the X chromosome leading to mutations of the dystrophin gene leading to proximal muscle weakness, lower limb before upper limb.

Other associated abnormalities include dilated cardiomyopathy, conduction abnormalities especially AV node.

BMD is milder than DMD.

Question 6

Presentation of homocysteinuria

Answer 6

Learning difficulties
Marfanoid features
Downward displacement of lens
Increased risk of VTE

Diagnosis via cyanide-nitroprusside test, which is also positive in cystinuria
Treated with replacement of pyridoxine

Question 7

Trinucleotide repeats in the following diseases:

Fragile X
Huntington’s
myotonic dystrophy
Friedreich’s ataxia*

Answer 7

Fragile X (CGG)
Huntington’s (CAG)
myotonic dystrophy (CTG)
Friedreich’s ataxia (GAA)

Question 8

HLA associations

HLA DQ2/DQ8
HLA DR3
HLA DR4
HLA DR2

Answer 8

DQ2/DQ8 - coeliac disease

DR3 - dermatitis herpetiformis, sjogrens syndrome, PBC

DR4 - Type 1 DM, RA

HLA DR2 - narcolepsy, goodpastures syndrome

Question 9

Difference between Kallman syndrome and Kleinfelter syndrome

Answer 9

Klinefelter’s - LH & FSH raised

Kallman’s - LH & FSH low-normal

Question 10

What is the most common cause of female carrier x linked mutation manifesting the disease?

Answer 10

Skewed X inactivation (Lyonisation)

Question 11

What defines a autosomal dominant pedigree?

Answer 11

Male to male transmission

Does not skip a generation

Question 12

Describe DNA linkage analysis

Answer 12

DNA polymorphism is used to find association with a specific clinical phenotype within the family group, ie, the gene itself does not need to be known.

Question 13

Definition of point mutation.

3 types of point mutations

Answer 13

Point mutation is a single base change.

1. Silent mutation - a DNA sequence change that does not change the amino acid sequence (due to degeneracy of DNA code)
2. Missense mutation - a single base change that results in a single amino acid change.
3. Non-sense mutation - single base change results in stop codon resulting in truncating mutation.

Question 14

Describe 2 types of truncating mutation

Answer 14

1. Frameshift mutation - DNA change that affects the normal triplet reading frame of the DNA code
2. Nonsense mutation - type of point mutation which changes the amino acid into a stop codon.

Question 15

Describe the role of siRNA (small interfering RNA)

Answer 15

Involved in RNA interference - a mechanism that inhibits gene expression, usually by causing the degradation of specific RNA molecules, but also by hindering the transcription of specific genes.

Question 16

3 ways in which dominant gene mutations exert their effect

Answer 16

1. Haploinsufficiency - loss of function mutation leading to a single functional copy of a gene, and that single copy does not produce enough product to display the wild type’s phenotypic characteristics
2. Dominant negative - interferes with the remaining single functional gene product. Worse than haploinsufficiency.
3. Gain of function - protein product with increased activity or toxic effect (eg huntington’s disease, all oncogenes)

Question 17

Definition of hemizygosity

Answer 17

The genotypic state in which one of two copies of a gene is absent is called hemizygosity.

Hemizygosity is not the same as haploinsufficiency; hemizygosity describes the genotype, and haploinsufficiency is a mechanism that may have caused the phenotype

Question 18

Role of SNPs in genetic diseases

Answer 18

SNPs can have a direct impact on health and cause a phenotype by itself.

However SNP-phenotype correlation may also occur due to SNP’s proximity to the genetic factor that is actually the cause of the disease (linkage disequilibrium).

Question 19

Define aneuploidy

Answer 19

Numerical abnormalities of whole chromosomes.

Can include trisomy, monosomy.

Question 20

What is the clinical significance of balanced chromosome rearrangement?

Answer 20

Balanced chromosome rearrangement usually results rearrangement without net gain or loss of chromosome material, therefore phenotypes are normal.

Abnormal phenotype results when breakpoint interrupts one or more critical genes.

Clinically, can cause problems for reproduction resulting in infertility, miscarriages, rarely birth of a child with multiple congenital abnormalities

Question 21

Describe Robertsonian translocation

Answer 21

Involves 2 acrocentric chromosomes (13, 14, 15, 21, 22) resulting in only 45 chromosomes in a karyotype.

(ie, p arm is so short that majority of the chromosome is q arm and the centromere)

Question 22

How do you detect microdeletions?

Answer 22

Via FISH markers. They will not be observed on routine karyotyping.

Question 23

Describe uniparental disomy

Answer 23

Occurs when both copies of a chromosome pairs are derived from the SAME parent. Typically a result of trisomy rescue in early embryonic life (ie, when 2 copies from same parent and 1 copy from the other parent results in trisomy, one of the chromosomes will be lost to conserve disomy)

One cause of abnormal imprinting pattern.

Question 24

Describe the pathogenesis of Prader-Willi and Angelman syndrome

Answer 24

Both occurs due to deletion of 15q12.

Prader-Willi is due to loss of function mutation in the PATERNALLY derived Ch15.

Angelman is due to loss of function mutation in the MATERNALLY derived Ch15.

Both diseases can occur as a result of maternal/paternal inheritance or due to uniparental disomy.

Question 25

6 Unique features of mtDNA

Answer 25

1. Maternal inheritance
2. Multiple copies inside each mitochondrion (2-10)
3. High mutation rate
4. Exhibit heteroplasmy - coexistence of mutant and wild type mtDNA
5. mtDNA bottleneck - in early oogenesis, a small number of genomes are selected to repopulate the oocyte. Depending on whether normal or pathogenic mtDNA is selected, that oocyte may result in forming zygote with severe/normal phenotype
6. Threshold effect - minimal critical number of mutant mtdNA is needed for each tissue to become dysfunctional.

Question 26

Haplotype

Answer 26

Group of alleles which are associated closely together at a specific genetic locus