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FRCPath Genomics > 03 - further disorders > Flashcards

03 - further disorders Flashcards

1
Q

Name 3 group of Lysosomal storage disorders (LSDs)

A 
1) Muccopolysaccharidosis (MPS)
> MPSI - Hurlers
> MPSII - Hunters
> MPS III - Sanfilippo Syndrome
> MPS IV - Morquio

2) Oligosaccharidosis
> I-cell disease
> Schlinder’s

3) Sphingolipidosis
> Tay Sach (HEXA)
> Fabry (GLA)
> Neiman Pick A/B

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2
Q

What are the genetic causes of a-thalassamia

A

> Haemoglobin (Hb) made up of alpha and beta chains in a tetamer
most common a2b2
2 genes encode a-globin - HBA1 and HBA2 (4 alleles in total)
carrier rates high in regions of malaria endemic
mutation type - mostly gene deletions:

> 1 del: Silent carrier
2 del: a-thal minor (asymptomatic)
3 del: a-thal = HbH disease (due to lack of a-globin, a tetramer of 4x b-globin chains formed)
4 del: Hb Barts hydrops fetalis syndrome

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3
Q

What are the genetic causes of b-thalassamia

A

> unlike a-globin, b-globin encoded by a single gene
mutation type also different = SNVs.
due to mutation type, can be either no expression of reduced activity of protein

3 types:
> B-thal Major: most severe type. Severe anemia & hepatosplenomegaly. Infant onset. Transfusions required

> B-thal intermediate: Later onset, milder anaemia

> B-thal minor: asymptomatic

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4
Q

What are the two main types of inherited cardiac disorders

A

1) Cardiomyopathy

2) Ion channelopathies (cardiac arrhythmias)

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5
Q

What are the types of Cardiomyopathy. what are the main genes

A

1 - Dilated Cardiomyopathy (DCM)
> 30% TTN
> MYH7

2 - Hypertrophic Cardiomyopathy (HCM)
> proteins involved in sarcomere
> MYBPC3
> MYH7

3 - Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
> PKP2
> DSP
> RYR2

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6
Q

What are the types of Ion channelopathies (cardiac arrhythmias). what are the main genes

A

1 - Long QT (LQT)
> potassium channel mutations result in delay after each heart beat
> KCNQ1
> KCNH2

2 - Brugada
> typical trace on ECG
> SCN5A
> CACNA1C

3 - Catecholaminergic polymorphic ventricular tachycardia (CPVT)
> exercise, stress and emotion induced cardiac instability
> Syncope (fainting) during exercise
> RYR2

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7
Q

What is sexual determination

A

Genetic sex. determine by transcription factors

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8
Q

What is sexual determination

A

Process in which internal and external genitalia form in response to hormones

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9
Q

Outline the process of sexual determination

A

> Embryo’s default is female. Need male factors to drive male sexual development
Initially the gonadal ridge forms a biopotential gonad, which can go down the male or female pathway:

MALE:
> SRY positive. SRY promotes SOX9 expressin
> This drives the development of testis
> Leydig cells form and express testosterone
> Sertoli cells form and express AMH (anti-mullerian hormone)
> Testosterone drives development of Wolffian ducts which become Vas deferens
> AHM drives regression of the Mullerian duct

FEMALE:
> SRY negative
> RSPO / WNT4 / B-catenin act to form ovary tissue
> in the absence of SRY, the Wolffian duct regress
> The Mullerian ducts develop which form the fallopian tubes, uterus and vagina

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10
Q

What can give rise to a FEMALE with 46,XY karyotype (e.g. 46,XY DSD)?

A

1) Disorders of testicular development (complete of partial gonadal dysgenesis):
> Swyer Syndrome (complete)
- appear normal female, normal external female genitalia and mullein ducts present. But do NOT have ovaries
- as no ovaries, they do not undergo puberty - so often detected from delayed puberty investigations
> instead of ovaries, they have streak gonads present - **risk of gonadoblastoma! **(often removed surgery)
> usually due to SRY deletion / LOF mutation

2) Disorder of Androgen synthesis
> androgens responsible for development of male ext genitalia.
> lack of androgen can result in mild hypospadias to complete female ext. genitalia

3) disorders of androgen response
> AIS - due to mutations in the AR gene
> partial or complete

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11
Q

What can give rise to a MALE with 46,XX karyotype (e.g. 46,XX DSD)?

A

> Male external genitalia range from ambiguous to normal
XX males often short stature, small testis and maldescended testis
hypogonadism and gynaecomastia common
90% are SRY +ve
other mutations inc: SOX9 dup

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12
Q

CF is the most common AR disorder. What are the presenting signs of classical CF

A 
> Elevated Cl in sweat
> Breathing difficulties due to build up of mucus
> frequenct pseudomonas infections
> pancreatic insufficiency
> Raised IRT on newborn blood spots
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13
Q

What are the 5 mutations classes seen in the CFTR gene. Give an example of each

A

1) No synthesis / protein expression
- truncating mutations such as G542X

2) Block in Processing
- protein misfolding and retained in ER = protein degraded
- F508del

3) Block in Regulation (Gating Defects)
- reduced capacity of CFTR protein to secrete Cl ion due to defects in channel ACTIVATION
- either defects in ATP binding domain or phosphorylation of R domain
- G551D

4) Altered conductance
- reduced capacity of Cl- conductance across membrane
- due to mutations within transmembrane domains
- often milder phenotype
- R117H

5) Regulation of other ion channel
- mutations in CFTR which affect function of other channel proteins such as ENaC sodium channel
- Deletion of Start Codon

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14
Q

What drugs are available to treat CF

A

> Ivcaftor - target gating defect mutations - G551D

> Lumacaftor - targets F508del

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15
Q

what 3 disorders are associated with FMR1 expansions

A

> Fragile X
FXTAS (FraX associated tremor ataxia syndrome)
POI

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16
Q

What is the proposed pathogenesis of DM1 RNA mediated GoF

A
  • in DM1 the repeat is in the 3’UTR = non-coding, but is transcribed into mRNA
  • proposed the expansion (CTG)n interferes with RNA processing
  • CUG repeats in pathogenic rage, fold into hairpins which accumulate and trap essential RNA-binding proteins:
    CUGBP1 + MBNL1
  • these to proteins have function in regulating splicing and so impairment of these leads to a global impact upon RNA processing & splicing
17
Q

What is unique to FSHD compared to other repeat disorders

A

> Repeats (D4Z4) are large (3kb each) & encode the DUX4 transcript on 4q35
Rather than expansion, repeat contraction causes FSHD

18
Q

Tell me about FSHD

A

> FSHD - facioscapulohumeral muscular dystrophy
result from aberrant expression of DUX4 transcript
DUX4 is a gremline TF, normally repressed through silencing of the region
FSHD requires a ‘permissive genotype’
polymorphisms distal to D4Z4 on4q35 = 4qA and 4qB
only the 4qA polys create a polyadenylation signal required for DUX4 expression

19
Q

What are the normal and pathogenic repeat ranges in FSHD

A 
Normal = 11-100 rpts
Pathogenic = <10 rpts

Contraction of D4Z4 repeats results is reduction of CpG islands, leads to reduction in methylation = relaxation of epigenetic silencing = expression of DUX4 (only on a 4qA background)

20
Q

What is a lysosome

A

membrane bound organelle (vesicle) with acidic contents (maintained by a H+ proton pump)

21
Q

Can you provide an example of a very severe and a very mild form of LSD

A

> SEVERE = neonatal Gaucher

> MILD = Heterozygous female carriers of Fabry

22
Q

What are the presenting features of DCM, what genes are involved

A
  • Reduced Ventricular wall thickness
  • reduced force contraction
  • 30% due to TTN
23
Q

What are the presenting features of HCM, what genes are involved

A
  • asymmetric thickening of ventricular walls
  • obstruction of outflow
  • present with angina, palpitations, presyncope
  • common cause of SCD in young athletes
  • typically AD
  • most common cause is MYH7 mutations
24
Q

What are the presenting features of ARVC, what genes are involved

A
  • progressive loss of cardiomyocytes
  • replacement of myocardium with fatty or fibre-fatty tissue
  • presents with ventricular arrhythmias, heart palpitations and syncope
  • PKP2, DSP, RYR2
25
Q

what is the WHO definition of infertility

A

failure to conceive clinical pregnancy after 12 months of regular unprotected sex

26
Q

What may be cause of male infertility

A
  • Aspermia (no semen)
  • Azoosperma (no sperm in ejactulate)
  • oligozoospermia (low sperm count)
  • asthenozoospermia (low sperm motility)
  • teratozoospermia (morphologically abnormal sperm)
27
Q

List 3 genetic causes of male infertility

A

1) Cytogenetic
2) Y Chr microdeletion
3) CFTR mutations

28
Q

What cytogenetic abnormalities are associated with male infertility

A

> NUMERICAL

  • 47,XXY
  • 45,X / 46,XY
  • 46,XX males

> STRUCTURAL

  • translocations / inversions - can lead to failure to complete synapses during pachytene and this induces cell death
  • marker chromosomes can interfere with homologue pairing during meiosis etc
  • ring chromosomes
  • Y chr isochromosome e.g. i(Y)(p10)
29
Q

How can CFTR mutations cause infertility

A

> During early embryo development, mucus clogs the devleloping Vas Deferens - results in its deterioration before birth
Congenital bilateral absence of Vas deferens (CBAVD) - results in obstructive azoospermia

30
Q

What can cause female infertility

A

> Chromosome abnormalities

> POF

31
Q

What cytogenetic abnormalities can be found in infertile female

A

NUMERICAL:
- 45,X (and versions of this including mosaicism - numerical and/or structural)

STRUCTURAL:

  • X Chr structural abs can result in infertility if disrupt critical regions POF1 or POF2
  • Similarly t(X;A)
32
Q

What tests would you perform to a female referred with Premature Ovarian Failure

A 
> Cytogenetics to look for 
- X chr abnormalites
- Turner Syndrome
- Trisomy X
> Fragile X testing
33
Q

Name 4 possible mechanisms whereby a female could manifest an X linked disease only normally expressed in males

A

> Female carrier with skewed X inactivation
Deletion involving the X chromosome
X-chromosome rearrangement or complete lose of X chromosome (45,X)
Female with 2x mutations
UPD of X chromosome

FRCPath Genomics (12 decks)

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