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FRCPath Genomics > 02 - core disorders > Flashcards

02 - core disorders Flashcards

1
Q

Provide 2 examples of X-linked dominant disorder with male lethality

A

1) X-linked hypophosphateamia
- mutations in PHEX
- kidneys cannot absorb phosphates and thus lost in urine
- as phosphates needed for bone development:
- Rickets
- bone deformities
- short stature
- dental abnormalities

2) X-linked Alport Syndrome
- mutations in COL4A5
- kidney disorder
- SNHL
- eye disorders

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2
Q

Provide 3 examples of X-linked recessive disorder

A

1) DMD/BMD
- DMD gene deletions & SNVs

2) SBMA - spinal bulbar muscular atrophy (AKA Kennedy)
- CAG triplet repeat in exon1 of the AR gene

3) Androgen Insensitivity Syndrome (AIS):
- AR receptor SNVs
- Androgen receptor is receptor for testosterone, mutations in AR gene reduce cells sensitivity to testosterone which can lead to feminisation
- Complete AIS - 46,XY with female genitalia. Raised as girls often
- Partial AIS - 46,XY with ambiguous genitalia

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3
Q

Fill in the blanks:

Disease: HD
Gene:
Inheritance:
Repeat Type:
Coding / non-coding
A 
Disease: HD
Gene: HTT
Inheritance: AD
Repeat Type: polyQ - CAG
Coding
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4
Q

Fill in the blanks:

Disease: Fragile X
Gene:
Inheritance:
Repeat Type:
Coding / non-coding
A 
Disease: Fragile X
Gene: FMR1
Inheritance: X-Linked Dom
Repeat Type: CGG
non-coding
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5
Q

Fill in the blanks:

Disease: Myotonic Dystrophy 1
Gene:
Inheritance:
Repeat Type:
Coding / non-coding
A 
Disease: Myotonic Dystrophy 1
Gene: DMPK
Inheritance: AD
Repeat Type: CTG
 non-coding
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6
Q

Fill in the blanks:

Disease: Friedrich Ataxia
Gene:
Inheritance:
Repeat Type:
Coding / non-coding
A 
Disease: Friedrich Ataxia
Gene: FXN
Inheritance: AR
Repeat Type: GAA 
non-coding
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7
Q

Which triplet disorders result from Loss of Function

A

> Fragile X

> Friedreich Ataxia

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8
Q

Which triplet disorders result from Gain of Function

A

> Coding repeats (polyQ) - HD; SMBA; DRPLA; some types of SCAs

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9
Q

Name 4 polyQ triplet disorders

A

1 - HD
2 - SCA1,2,3
3 - DRPLA
4 - SBMA

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10
Q

Give 2 examples of non-coding triplets

A
  • Fragile X - (CGG)n repeat

- DM1 - (CTG)n repeat

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11
Q

Give 3 mechanisms found in AD disorders

A

1) Loss of Function - haploinsufficiency
2) Gain of Function
3) Dominant Negative

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12
Q

Give 3 examples of AD disorders resulting from LoF

A

1) HNPP - PMP22 gene
2) GLUT1 deficiency - SLC2A1 gene
3) HCM - MYH7 and MYBPC3 genes

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13
Q

Give 3 example2 of AD disorders resulting from GoF

A

1) CMT - PMP22
2) HD - polyQ (CAGn) expansion in HTT gene
3) Achondroplasia - FGFR3 gene

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14
Q

Give an example of an AD disorder resulting from Dominant negative action

A

Osteogenesis Imperfecta (OI)

  • caused by mutations in COL1A1 and COL1A2 genes, notably mutations in the (Gly-X-Y)n repeat in the triple helix.
  • Glycine is critical for the turn of the polypeptide chain, enabling three chains to rotate around one another to form a triple helix collagen fibre molecule
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15
Q

What is unique to polyAlanine repeats disorders?

A

> 4 nucleotide combinations can code for an Alanine codon, there at a nucleotide level, poly Alanine repeats are unpure repeats. This makes them stable and so are NOT prone to expansion - thus do not exhibit anticipation

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16
Q

What type of syndromes are associated with poly Alanine repeats and why?

A

> early onset, congenital malformation syndromes
polyalanine repeats often found in transcription factors where polyalanine repeats in ‘normal’ range for Beta sheets conferring resistance to enzymatic degradation

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17
Q

Give 3 examples of polyalanine repeat disorders

A

1) OPMD - oculapharyngeal muscular dystophy:
- PABPN1 gene
- late onset with ptosis, swallowing difficulties and limb weakness

2) SPD - synpolydactyly type II
- HOXD1B - homeobox transcription factor - involved in limb pattern development during embryogenesis

3) HFGS - hand feet genital syndrome
- HOXAB - homeobox transcription factor - involved in limb and genital development during embryogenesis

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18
Q

What is unique to OPMB compared to other polyalanine repeats

A

> Gene responsible is not a transcription factor

> disorder is NOT early onset

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19
Q

Name 5 mechanisms which can lead to imprinting disorders

A 
1 - UPD
2 -deletion
3 - duplication
4 - Mutation on active allele
5 - epimutation (e.g. loss/gain methylation)
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20
Q

Name 5 regions associated with an imprinting disorder

A 
> 6q24 - Transient Neonatal diabetes mellitus type I
> Chr7 - Silver Russell
> 11p15 - Beckwith Weidemann
> 14q32 - UPD14
> 15q11.2 - AS/PWS
21
Q

Tell me about Beckwith Weidemann Syndrome

A

> Chr11 - 11p15

> Key genes:

  • IGF2 (paternally expressed) growth factor
  • H19 (maternally expressed) - inhibits IGF2
  • CDKN1C (maternally expressed) -Cyclin dependant kinase inhibitor - inhibits cell growth

> Mechanisms:

  • hypomethylation of IC2 on maternal allele (loss of methylation)
  • paternal UPD (same as loss of maternal allele)
  • CDKN1C mutations
  • IC1 hypermethylation - results in H19 loss and thus bialleic expression of IGF2 (expressed on both mat & pat allele)
22
Q

what are the causes of PWS?

A

> deletion (70%)
UPD (30%)
Imprinting errors (2%)

23
Q

what are the causes of AS?

A 
> deletion (70%)
> UPD (5%)
> Imprinting errors (5%)
> Point mutations (10%)
> unknown (10%)
24
Q

Give 3 examples of 1 gene associated with more than 1 disorder

A

1) COL2A1
- Gly substitutions = achondrogenesis
- other missense = spondyloeipphyseal dysplasia
- mutations in ex12-24 = Kneist dysplasia
- Nonsense (LoF) = Stickler syndrome

2) PMP22
- GOF (inc. dups) = CMT
- LOF (inc.dels) = HNPP

3) AR
- SMBA
- Androgen Insensitivity Syndrome

25
Q

Provide 4 disorders associated with mitochondrial mutations

A

1) MELAS - m.3243A>G
2) MERRF - m.8344A>G
3) NARP - m.8993T>G
4) Aminoglycide Induced deafness - m.1555A>G

26
Q

What is the common MELAS mutation

A

m.3243A>G

27
Q

What is the common MERRF mutation

A

m.8344A>G

28
Q

What is the common Aminoglycide Induced deafness mutation

A

m.1555A>G

29
Q

Name 3 chromosome breakage disorders

A

1) Fanconi Anaemia
2) Bloom Syndrome
3) Ataxia Telangiectasia

30
Q

Tell me about Fanconi Anaemia

A

> 15 genes associated (FANCA, FANCB, FANCC etc)
congenital abnormalities, growth retardation, microcephaly
pancytopenia
susceptibility to haematological malignancy

TEST:
> as susceptible to cross-linking agents, treat with mytomicin C and count chromosome breakage.

31
Q

Tell me about Bloom Syndrome

A

> BLM gene - TSG encodes DNA helicase
BLM WT suppresses inappropriate recombination
loss of BLM = hyper-recombination

TEST:
> replication staining (treat early with thymidine, then with Brad - string differently).
> enables visualisation of SCE
> count SCE vs normal controls - Bloom = x10 more

32
Q

Tell me about Ataxia Telangiectasia

A

> ATM gene
cerebral & truncal ataxia due to neuronal death in brain
ATM gene encodes a serine tyrosine kinase involved in signalling pathway in response to dsDNA breaks
early onset
increased risk of cancer

33
Q

Give 3 examples of syndromes associated with marker chromosomes

A

1) Pallistar Killian Syndrome
> i(12p) = tetrasomy for 12p
> severe MR; Seizures; characteristic facies; diaphragmatic hernia
> need fibroblast cultures

2) Emmanuel Syndrome
> + der(22)t(11;22)
> derivative from a t(11;22) - due to 3:1 segregation
> severe ID, microcephaly, FTT; facial asymmetry

3) Cat Eye Syndrome
> inv dup 22
> tetrasomy 22p
> MR; Iris coloboma

34
Q

name the 9 genetic conditions currently screened by UK newborn screening programme

A 
1 - PKU
2 - CHT
3 - Sickle Cell
4 - CF
5 - MCADD
6 - MSUD
7 - Homocystinuria 
8 - GA1
9 - IVA
35
Q

What are the pedigree features in XLR disorders

A

> Affected father has 100% risk of having obligate carrier daughters and 0% risk of an affected son.
Carrier females have a 50% risk of an affected son, and 50% of carrier daughter

36
Q

What are the presenting features of DMD

A

> progressive & symmetrical muscle weakness
Gower’s sign
raised CK levels

37
Q

What is the carrier frequency of SMA

A

1 in 50

38
Q

What are the presenting features of SMA

A

> 60% present as ‘floppy baby’ - referred to as type I - most severe
Type II SMA presents 6-12mth with low muscle tone and inability to walk

39
Q

What is the inheritance of SMA. What is the responsible gene, what is its function?

A

> AR
SMN1
functions in spliceosome

40
Q

Provide an example of a Haploinsufficient gene. What disorder is associated with its loss

A

> ELN - elastin

> Williams Syndrome

41
Q 
In Fragile X, what are the repeat size ranges for:
Normal 
Intermediate
Premutation
Full mutation
A
  • Normal = 6-50 rpts
  • Intermediate = 46-58 rpts
  • Premutation = 55-200 rpts (unmethylated)
  • Full mutation = 200+ (methylated)
42
Q

Females carriers of premutations may develop______

A

Primary Ovarian Failure / insufficiency

43
Q

What are the presenting features of PWS

A
  • early infancy severe hypotonia (floppy baby)
  • early feeding difficulties
  • childhood hyperplasia (overeating) = Obesity
  • characteristic facies
  • motor milestones & language delay
  • short stature
  • behaviour issues, temper tantrums
44
Q

What are the presenting features of AS

A
  • Severe DevDel
  • poor / absent speech
  • LD
  • epilepsy
  • hyperactivity
  • unique behaviour - happy demeanour, fq laughing & smiling, hand flapping
  • ’ happy puppet’
45
Q

PWS is caused by the loss of the _________ allele

A

paternal

46
Q

AS is caused by the loss of the _________ allele

A

maternal

47
Q

The paternal allele expresses which genes in the PWS/AS region

A

SNURF / SNRPN (2 proteins expressed from single transcript)

48
Q

The maternal allele expresses which genes in the PWS/AS region

A

UBE3A - encodes an E3 ubiquitin ligase.

49
Q

What is the common test technique for PWS/AS referrals

A

MS-MLPA

FRCPath Genomics (12 decks)

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