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Week 3 Flashcards

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1
Q

Osteogensis Imperfecta is caused by what type of mutation + MoI?

A

mutation: in the gene COL1A1 or COL1A2 (encoding for the proα1(I) and proα2(I) chains of type I collagen)
MoI: Autosomal dominant

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2
Q

Osteogensis Imperfecta Type I CF?

A

1) Up to 100 fractures
2) no short stature
3) blue sclera
4) may have hearing loss

*Classic non-deforming (Type I)

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3
Q

Osteogenesis Imperfecta Type II CF?

A

1) Dark sclera
2) Rib fractures
3) Sever short stature
4) deforemed extremities
5) small thorax
6) Undermineralised skull

*Perinatal lethal (Type II)

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4
Q

CF of Type III Osteogenesis imperfecta

A
  • Fractures at birth
  • Progressive deformity
  • Marked short stature
  • Blue sclera
  • Frequent hearing loss
  • Dentinogenesis imperfecta

* Progressively deforming (Type III)

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5
Q

Osteogensis Imperfecta Type IV CF?

A

– Multiple fractures
– Mild to moderate deformity
– Variable short stature
– Normal to grey sclerae

* Common variable (Type IV)

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6
Q

what type of mutations cause mild, non-deforming Osteogenesis Imperfecta?

*Type I

A

loss of function mutations in the COLA1 gene (nonsense, frameshift, splicing abnormalities)
* results in the reduction of available proα1

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7
Q

What type of mutations cause sever cases of Osteogenesis Imperfecta?

*Type II-IV

A

Missense mutations in *COLA1A1/2 gene
*Have a dominant negative effect

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8
Q

CF of the Classical type of Ehlers-Danlos Syndrome

A

1) Skin:
– Hyperextensible skin (and hyperelastic)
– Fragile skin with abnormal wound healing
(e.g. dermal splitting over pressure points, widened and atrophic scars)
– Tendency to bruise (with staining)
– Fleshy lesions over knees and elbows
2) Joint hypermobility

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9
Q

MoI + Gene mutation of the Classical type of Ehlers-Danlos Syndrome

A

MoI: AD
mutation : COL5A1, COL5A2

* Variable expressivity

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10
Q

MoI of Hypermobility type Ehlers-Danlos Syndrom

A

AD
(unknown mutation type)

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11
Q

CF of Hypermobility type Ehlers-Danlos Syndrome

A
  • Joint hypermobility
  • Subluxations (dislocations)
  • Chronic pain and degenerative joint disease
  • Skin (normal or slightly hyperextensible)
  • Mild aortic root dilatation

* least severe type

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12
Q

MoI + mutation gene of Vascular type Ehlers-Danlos Syndrome

A

MoI: AD
Mutation in: COL3A1 gene (Type III collagen)

* **Genotype/ phenotype correlations **

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13
Q

CF of Vascular type Ehlers-Danlos Syndrome

A
  • Thin, translucent skin
  • Typical facial features:
    – Thin, narrow nose, prominent eyes
  • Fragility of:
    – Arteries
    – Intestines
    – Uterus

* Severe type

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14
Q

MoI + Mutation gene of Kyphoscoliotic Ehlers-Danlos Syndrome

A

MoI: AR
Mutation: in PLOD1 gene

* Rare condition

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15
Q

CF of Kyphoscoliotic EDS

A
  • Hypotonia and significant delay in motor milestones
  • Fragile sclerae (risk of rupture of globe)
  • Fragile skin, joint laxity
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16
Q

MoI+ Mutant gene in Mrafan Syndrome

A

MoI: AD (CT disorder)
Mutation: in FBN1 gene , 15q11 (fibrilin gene)

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17
Q

CF of Marfan syndrome?

A

– Ectopia lentis (lens displacement)
– Aortic root dilatation*
– Systemic score (use table, 7 or more)

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18
Q

* Marfan syndrome

FBN1 mutations are app.:
—- % inherited
—- % de novo

A

– 75% inherited
– 25% de novo

* No definitive genotype/ phenotype correlation
* Variable expressivity

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19
Q

Instability of triplet repeats is a type of ———— mutation

A

insertion

* slipping mispairing during DNA replication

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20
Q

The 2 types of triplet repeat mutations+ disorders

A

1) Expansion in the coding part
– encoded protein has gained a new function (e.g.
Huntington, most types of Spinocerebellar Ataxias, Kennedy disease)

2) Expansion in the non-coding part
– Disturbs protein expression/ function (e.g. Fragile
X syndrome- UTR, Friedreich’s ataxia- intron)
– RNA assumes new function (e.g. Myotonic
dystrophy 1 - UTR, Myotonic dystrophy 2 - intron)

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21
Q

In Huntington disease, Age of onset correlates w/ number of repeats.
– Adult onset: —- repeats
– Juvenile onset: —— repeats

A

– Adult onset: up to 55 repeats
– Juvenile onset: > 60 repeats

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22
Q

In Huntington disease Anticipation is observed. However, more commonly in [Paternal/maternal] transmission

A

Paternal

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23
Q

CF of Fragile X-syndrome

A

1) Intellectual disability
2) Dysmorphic features: long face, prominant chin and ears
3) Joint laxity (“loose joints”)
4) Large testes after puberty

24
Q

MoI of Fragile X-syndrome+ Mutant gene

A

MoI: Gain of Fxn (In frame insertion) , X-linked recessive (M>F)
Mutation: in FMR1 gene
( CGG repeats in the untranslated region (UTR) of exon1 of the FMR1 gene)

25
Q

*Fragile X-syndrome

Normal CGG allele repeats?

A

5-44 repeates

26
Q

*Fragile X-syndrome

intermediate alleles of CGG repeats

A

45-54 repeats
– Not pathogenic but may expand into premutation if
passed on by females

27
Q

premutation allele for Fragile X-syndrome

A

55-200 CGG repeates
– Associated with risk for FXTAS and POI
– May expand into full mutation if passed on by females

28
Q

Full muation allele for Fragile X-Syndrome

A

> 200 CGG repeats
- Causes Fragile X syndrome (males affected more severely than women)

29
Q

CF of Fragile X tremor/ ataxia syndrome (FXTAS)

A

– Progressive ataxia and intention tremor
– Late onset

30
Q

CF of Fragile X-associated Primary Ovarian Insufficiency (POI)

A

Menopause before the age of forty

31
Q

CF of Myotonic Dystrophy type 1 (DM1)

A

1) muscle weakness (Hypotonia), Myotonia
2) Cataracts
3) Endocrine multiple disorders
4) Cardiac Conduction defecs
5) Intellectual disability
6) Ptosis, facial wekness

*Hypotonaia may lead to respiratory compromise (failure)

32
Q

*Myotonic Dystrophy

MoI of DM1 + mutation

A

MoI: AD (Anticipation mostly in materanl inheritance)
mutation: CTG repeat expansion at the DMPK gene (untranslated regoin)

33
Q

* Myotonic Dystrohy Type 1

Normal CTG repeats

A

5-34 repeats

34
Q

premutation (intermediate) alleles causing DM1

A

35-49 CTG repeats
– Asymptomatic but can expand in subsequent generations

35
Q

Full penetrance (full mutation) alleles for DM1

A

> 50 CTG repeats
– Larger repeats correlate with earlier onset and increased severity (e.g. more than 1000 repeats with congenital disease)

36
Q

Anticipation is Observed in Myotonic Dystrophy Type 1. However, it is mostly observed in [Paternal/Maternal] inheritance

A

Maternal

37
Q

Clinical syndromes w/ Copper/ Iron regulation

A

1) Wilson disease
2) Haemochromatosis

38
Q

Channelopathies CF ?

A

1) Nervous (epilepsy, ataxia, blindness, deafness)
2) Cardiac (Arrythmias, sudden cardiac arrest)
3) Respiratory - CF

39
Q

————–: disease casued by defects in ion channels (e.g, CF)

A

channelopathies

40
Q

MoI of Cystic fibrosis+ gene affected?

A

MoI: AR
Mutation: in the CFTR gene
(reduced Cl- and HCO-3 transport)

* genotype/ phenotype relates to the pancreatic function

41
Q

CF of CF?

A

1) Airways and sinuses:
– Recurrent bronchitis, sinusitis
– Progressive obstructive airway disease
– Recurrent infections
2) Gastrointestinal:
– Pancreatic insufficiency and malabsorption
– Meconium ileus
– Pancreatic/ chronic hepatic disease
3) Sweat gland abnormalities (hyponatraemic
dehydration)*
4) Azoospermia (abnormal vas deferens)
– Congenital Absence of Vas Deferens (CAVD) is described as a distinct phenotype/ condition at the mild end of CF spectrum

42
Q

* Mutation

CF Class #: abnormal channel activation (gating)

A

CLASS III

43
Q

* mutation

CF Class # : abnormal Chloride conductivity

A

CLASS IV

44
Q

CF Class #: reduced stability (increased turnover

A

CLASS VI

45
Q

CF Class #: non-coding mutations lead to reduced synthesis

A

CLASS V

46
Q

CF Class # : abnormal CFTR processing (e.g. F508del)

A

CLASS II

47
Q

CF Class #: nonsense/ frameshift mutations (e.g. G542X)

A

CLASS I

48
Q

MoI+ Mutation in Wilson disease

A

MoI: AR
Mutation: in the ATP7B gene (Excessive Copper metabolism)

49
Q

CF of Wilson disease

A

1) Hepatitis, hepatic failure, chronic disease
2) Movement disorders
3) Depression
4) Copper deposition in the cornea- Kayser-Fleischer rings

50
Q

Diagnosis of Wilson disease:
Copper analysis show [low/high] serum copper and ceruloplasmin

A

Low

51
Q

MoI + mutation of Hereditary Haemochromatosis

A

MoI : AR, reduced penetrance
Mutation: in the HFE gene (high iron levels)

52
Q

CF of Haemochromatosis

A

1) Joint pain
2) skin pigmentation
3) Cardiomyopathy
4) DM

*liver Cirrhosis is a complication as the disease progresses

53
Q

LAb Diagnosis of Haemochromatosis?

A

elevated transferriniron saturation and ferritin concentration

54
Q

Clincial case

  • 17-year-old male
  • ‘Marfanoid’ habitus
  • Distinctive features (prominent lips)
  • Unusual tongue lesions
  • Family history of cancer (Phaeochromocytoma, Thyroid cancer)

Syndrome+ MoI +Mutation

* Marfanoid habitus –> symptoms resembling those of Marfan syndrome

A

Syndrome : Multiple Endocrine Neoplasia Type 2 (MEN2B)
MoI: AD
Mutation: Activating mutation of RET

55
Q

MEN2A/B or both syndroms

A
  • Oncogenesis
  • Medullary thyroid carcinoma (A, B)
  • Phaeochromocytoma (A, B)
  • Parathyroid adenoma/ hyperplasia (A)
  • Mucosal neuromas (B)
  • Ganglioneuromatosis of GI tract (B)

Medical Genetics (8 decks)

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