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Medicine Year 2 > Scenario 33 > Flashcards

Scenario 33 Flashcards

1
Q

What are mendelian disorders?

A

Caused by a single gene

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2
Q

What is compound heterozygosity?

A

Different mutations within the same gene (eg CF)

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3
Q

What are the key features of an autosomal dominant condition?

A

50% chance of passing on, affected individuals are heterozygous
KEY- MALE TO MALE TRANSMISSION
Variable penetrance, variable expression
Mutations can be Inherited from carriers or de novo

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4
Q

What are the key features of autosomal recessive conditions?

A

Both male and female affected
25% chance of passing on and 50% chance of carrier
25% unaffected
Common in consaginous relationships

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5
Q

What are the key features of X-linked recessive disorders

A

Only males related via the female line are usually affected
Women usually asymptomatic
1 in 2 chance that each son born to a carrier female is affected and 1 in 2 chance that each daughter will be a carrier
All daughters of an affected male are carriers
Sons of an affected male are not affected NO MALE TO MALE TRANSMISSION
Females can be affected- non random inactivation leading to a chance expression in certain tissues

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6
Q

What is X inactivation?

A

Only one X used per cell so one X is switched off before blastocyst implantation in female embryos
All of its daughter cells have the same X inactivated

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7
Q

What are the key features of X-linked dominant disorders

A

Males and females affected (more males)
Can be lethal in males
50% risk to offspring from affected mothers
All daughters of affected males inherit
No sons of affected males inherit (X comes from the mother) NO MALE TO MALE TRANSMISSION

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8
Q

What does a standard karyotype test show?

A

Changed chromosome number, structure, translocations

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9
Q

What is the limit of standard karyotype testing?

A

as small as 10Mb (chromosome is 100Mb)

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10
Q

How does aneuploidy arise?

A

When you get non dysjunction in a gamete (split unevenly) and that gamete fertilises
Such as Downs syndrome, patau syndrome (trisomy 13), edwards syndrome (trisomy 18) or sex chromosome eg Turners syndrome 45,X

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11
Q

What are the signs of Turners syndrome?

A

short stature, peripheral oedema, amenorrhoea, normal intelligence

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12
Q

Why does translocation not always have an effect?

A

It depends on which chromosomes are inherited can be unbalances with a partial monosomy or one chromosome and a trisomy of another

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13
Q

When is FISH used?

A

When you know specifically what you are looking for- fluorescent probe to highlight a particular abnormality

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14
Q

What conditions is FISH used to identify?

A

CATCH-22- conotruncal abnormality, cleft lip/palate, absent thymus and PT glands, learning difficulties

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15
Q

What are the advantages of comparative genomic hybridisation array?

A

Detailed karyotype to find small genomic inbalances in seemingly normal karyotypes e.g. Susceptibility Can see 100kb

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16
Q

When is single gene testing useful?

A

For diagnosis, management, recurrence risk and relative risk eg. Achondroplasia (FGFR mutation) or to distinguish between duchenne or becker muscular dystrophy

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17
Q

What is mocaicism

A

Later in development a cell acquires a mutation and all daughter cells from that one have the mutation but the others are normal- somatic can give mild features of a condition, germ line can give a future recurrence risk

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18
Q

What is NGS?

A

Test 95% of genome in one test- huge amount of data but ethical issues in finding out susceptibility information

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19
Q

What is incomplete penetrance?

A

The likleihood of the condition causing the phenotype so the risk of a child being affected is the probability of the mutant allele being inherited x penetrance

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20
Q

How do we calculate risk of autosomal recessive disorders in populations with no family history?

A

Hardy-Weinburg ratio

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21
Q

What are the key feature of the Hardy-Weinburg ration?

A 
AA=pxp
Aa=pq (twice)
aa=qxq
p+q=1 and p2+2pq+q2=1
disease incidence=qxq (square root to find q then work out p etc)
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22
Q

What are the key features of CVS?

A

taken in first trimester after 11 weeks, chromosome analysis after culture (2 weeks) 1-2% risk of miscarriage

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23
Q

What are the key features of amniocentesis?

A

10-20ml of amniotic fluid taken at 16 weeks cultured for 2 weeks 0.5-1% risk of miscarriage (would need a medical termination if decided)

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24
Q

What single base changes conserve the base chemistry?

A

C-T T-C G-A A-G

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25
Q

Why are there more transitions than transversions?

A

Because its easier to keep the base the same

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26
Q

What are common consequences of variants in splice recognition elements?

A

Depend on the relative strengths of the elements

Exon skipping, use of cryptic splice sites and intron retention

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27
Q

Where are some other sites of functional variation?

A

Promotors, untranslated regions or polyadenylation signals

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28
Q

What is an amorph?

A

Complete loss of gene function

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29
Q

What is a hypomorph?

A

Partial loss of gene function

30
Q

Why do these loss of function variants arise?

A

Little or no protein produced, protein unstable or a residue/domain essential for function is missing or altered

31
Q

What is haploinsufficiency?

A

Organism so sensitive to loss that 50% loss causes a phenotype

32
Q

What is the dominant negative effect?

A

Not only does the protein lose its function but disrupts normal alleles function too

33
Q

What is a somatic second hit?

A

Organism largely normal but somatic 2nd mutations give rare clones of null cells which are defective

34
Q

What is an antimorph?

A

A variant where dominant alleles act in opposition to normal gene activity

35
Q

What is a neomorphic gene?

A

Variants that cause a dominant gain of function different to normal function

36
Q

What is genetic linkage?

A

That 2 DNA regions close together are more likely to be co-inherited in recombination

37
Q

What is the LOD score?

A

Used to detect the presence of linkage =log10 L(linkage)/ L(no linkge)
>3 linkage

38
Q

What do we do once we have worked out the 2 regions are linked?

A

Identify the genes located within and assess according to biological function, sequence them and find the causative mutation

39
Q

What % of spontaneous abortions are aneuplodies?

A

50

40
Q

What is the main cause of aneuploidy?

A

Meiotic non-dysjunction (mainly in females)

41
Q

What are the main features of Downs syndrome?

A

mental disability, dysmorphic features, cardiac defects, 1 in 700 births, primary trisomy or translocation

42
Q

What are Robertsonian Translocations?

A

Formed by the fusion of 2 acrocentic chromosomes (short p- 13,14,15,21 and 22) giving a chromosome number of 45 but a normal phenotype, happens in 2/1000 births and provides reproductive risks
2 long arms fuse and 2 short arms fuse- short one contains useless DNA and is lost leaving just the long- all the useful DNA present but may provide problems when being passed on

43
Q

What are the main features of Edwards syndrome?

A

Severe mental disability, dysmorphic (micrognathia, prominent occiput), clenched overlapping fingers, rocker bottom heels and cardiac defects, 1 in 3000, 30% die in 1 month, 90% in 1 year, trisomy 18 and translocation

44
Q

What are the main features of Patau syndrome?

A

severe mental disability, cleft lip and palate, holoprocencephaly, postaxial polydactyly, renal abnormalities, cardiac defects, 1 in 5000 45% die in 1 month, 95% in 1 year, trisomy 13 and translocation

45
Q

What are the main features of Turner syndrome?

A

normal intelligence, webbed neck, broad chest, wide nipples, primary amenorrhoea, lack of secondary sexual characteristics, coarctation of the aorta, 1 in 5000, 45 X, 80% paternal orgin

46
Q

What are the main features of Klinefelter syndrome?

A

taller than average, long limbs, 30-50% gynaecomastia, infertility, reduced IQ, 1 in 1000, 47XXY

47
Q

What are reciprocal translocations?

A

Exchange of material between 2 non-homologous chromosomes (1 in 500) balanced carriers are generally phenotypically normal

48
Q

What are the main features of Wolf-Hirschorn? (del 4p)

A

severe mental disability, frontal bossing, hypertelorism, carp shaped mouth, beaked nose

49
Q

What are the main features of Cri du chat? (del 5p)

A

moderate to severe mental disability, cat like cry in infancy, slow growth

50
Q

How do you detect sub microscopic deletions?

A

molecular cytogenic techniques, targeted testing based on clinical signs- FISH

51
Q

What are the main features of Williams syndrome?

A

1 in 10000, elfin face, heart defects, hypercalcaemia, learning difficulties, 1.5Mb deletion of ELN and LIMK1 genes

52
Q

What are the main features of Angelman syndrome?

A

severe mental disability, abnormal speech, movement or balance disorder, happy disposition, seizures, open mouth, protruding chin
Lack of maternally imprinted genes on chromosome 15

53
Q

What are the main features of Prader-Willi syndrome?

A

Mild to moderate mental disability, hypotonia, failure to thrive, hypogonadism, obesity, growth retardation, small hands and feet, almond shaped eyes
Lack of paternally imprinted genes

54
Q

What are cytogenetics?

A

The study of genetic constitution of cells through the visualisation and analysis of chromosomes- G banding, microarrays and other molecular techniques (FISH, MLPA) can be performed postnatally or prenatally

55
Q

When would you use G banding?

A

When the signs are diagnostic of a balanced rearrangement (normal phenotype but infertile)

56
Q

When would you use array CGH?

A

When a chromosome imbalance is suggested

57
Q

What is in the human mitochondrial gene?

A

2 rRNA genes, 22 tRNA genes, 13 protein coding sequences, 1000-10000

58
Q

How are mitochondria inherited?

A

Via the oocyte not the sperm

59
Q

What is heteroplasmy?

A

The ratio of the no of mutant mitochondria: healthy mitochondria depends whether a phenotype will be seen

60
Q

How can you predict the severity of a mitochondial disorder?

A

Roughly correlated with the mutant load in affected tissues

61
Q

What is epigenetics?

A

The study of heritable changes that occur without a change in DNA sequence (bases stay the same), inherited faithfully through cell division

62
Q

Are epigenetic changes reversible?

A

yes

63
Q

How does differentiation by directing gene expression happen?

A

Epigenetics

64
Q

What different mechanisms of epigenetic modifications are there?

A

DNA methylation, post-translational modifications to histone proteins and small/ non coding RNAs

65
Q

How is the DNA methylated?

A

Methylation of one of the existing bases (cytosine) resulting in alterations in gene expression and phenotype- doesnt affect bonding with guanine

66
Q

What diseases are linked to epigenetics?

A

Imprinting disorders, broad range of cancers and tumours, neurological disease (Rett, AD, PD, and HD), psychiatric disorders (autism, bipolar, schizophrenia), heart disease, AI disease

67
Q

What are imprinted diseases?

A

Inherited form only one parent
150 known eg. PWS, AS, beck with-wiedemann syndrome, silver-russell syndrome, transient neonatal diabetes
Associated with imprinting- susceptibility to bipolar, mani depression, autism, schizophrenia

68
Q

What happens if whole genome is from one parent not just a small part?

A

Parthenogenetic (2 maternal)- no placenta, hyperdifferentiation
Androgenetic (2 paternal)- placenta out of control

69
Q

What are the main features of albrights hereditary osteodystrophy

A

associated with GNAS, problem with PTH, short metacarpals and metatarsals, phalanges and wide bones

70
Q

What are the main features of Beckwith-Wiedemann Syndrome?

A

1 in 14,000 large tongues eyes, body size, hernia of the naval and small head
Cancer disposition
NLRP2

71
Q

What are the main features of Silver-Russell syndrome?

A

Low birth weight, triangular face, poor appetite ICF2

72
Q

What gene is involved in transient neonatal DM?

A

zfp57

Medicine Year 2 (19 decks)

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