Week 3

Question 1

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

Answer 1

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

Question 2

Osteogensis Imperfecta Type I CF?

Answer 2

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

*Classic non-deforming (Type I)

Question 3

Osteogenesis Imperfecta Type II CF?

Answer 3

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

*Perinatal lethal (Type II)

Question 4

CF of Type III Osteogenesis imperfecta

Answer 4

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

* Progressively deforming (Type III)

Question 5

Osteogensis Imperfecta Type IV CF?

Answer 5

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

* Common variable (Type IV)

Question 6

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

*Type I

Answer 6

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

Question 7

What type of mutations cause sever cases of Osteogenesis Imperfecta?

*Type II-IV

Answer 7

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

Question 8

CF of the Classical type of Ehlers-Danlos Syndrome

Answer 8

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

Question 9

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

Answer 9

MoI: AD
mutation : COL5A1, COL5A2

* Variable expressivity

Question 10

MoI of Hypermobility type Ehlers-Danlos Syndrom

Answer 10

AD
(unknown mutation type)

Question 11

CF of Hypermobility type Ehlers-Danlos Syndrome

Answer 11

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

* least severe type

Question 12

MoI + mutation gene of Vascular type Ehlers-Danlos Syndrome

Answer 12

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

* **Genotype/ phenotype correlations **

Question 13

CF of Vascular type Ehlers-Danlos Syndrome

Answer 13

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

* Severe type

Question 14

MoI + Mutation gene of Kyphoscoliotic Ehlers-Danlos Syndrome

Answer 14

MoI: AR
Mutation: in PLOD1 gene

* Rare condition

Question 15

CF of Kyphoscoliotic EDS

Answer 15

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

Question 16

MoI+ Mutant gene in Mrafan Syndrome

Answer 16

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

Question 17

CF of Marfan syndrome?

Answer 17

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

Question 18

* Marfan syndrome

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

Answer 18

– 75% inherited
– 25% de novo

* No definitive genotype/ phenotype correlation
* Variable expressivity

Question 19

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

Answer 19

insertion

* slipping mispairing during DNA replication

Question 20

The 2 types of triplet repeat mutations+ disorders

Answer 20

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)

Question 21

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

Answer 21

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

Question 22

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

Answer 22

Paternal

Question 23

CF of Fragile X-syndrome

Answer 23

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

Question 24

MoI of Fragile X-syndrome+ Mutant gene

Answer 24

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)

Question 25

# *Fragile X-syndrome Normal CGG allele repeats?

Answer 25

5-44 repeates

Question 26

# *Fragile X-syndrome intermediate alleles of CGG repeats

Answer 26

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

Question 27

premutation allele for Fragile X-syndrome

Answer 27

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

Question 28

Full muation allele for Fragile X-Syndrome

Answer 28

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

Question 29

CF of Fragile X tremor/ ataxia syndrome (FXTAS)

Answer 29

– Progressive ataxia and intention tremor – Late onset

Question 30

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

Answer 30

Menopause before the age of forty

Question 31

CF of Myotonic Dystrophy type 1 (DM1)

Answer 31

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)

Question 32

# *Myotonic Dystrophy MoI of DM1 + mutation

Answer 32

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

Question 33

# * Myotonic Dystrohy Type 1 Normal CTG repeats

Answer 33

5-34 repeats

Question 34

premutation (intermediate) alleles causing DM1

Answer 34

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

Question 35

Full penetrance (full mutation) alleles for DM1

Answer 35

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

Question 36

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

Answer 36

**Maternal**

Question 37

Clinical syndromes w/ **Copper/ Iron regulation**

Answer 37

1) Wilson disease 2) Haemochromatosis

Question 38

Channelopathies CF ?

Answer 38

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

Question 39

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

Answer 39

channelopathies

Question 40

MoI of Cystic fibrosis+ gene affected?

Answer 40

MoI: AR Mutation: in the CFTR gene (reduced Cl- and HCO-3 transport) | * **genotype/ phenotype relates to the pancreatic function**

Question 41

CF of CF?

Answer 41

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

Question 42

# * Mutation CF Class **#**: abnormal channel activation (gating)

Answer 42

CLASS III

Question 43

# * mutation CF Class **#** : abnormal Chloride conductivity

Answer 43

CLASS IV

Question 44

CF Class **#**: reduced stability (increased turnover

Answer 44

CLASS VI

Question 45

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

Answer 45

CLASS V

Question 46

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

Answer 46

CLASS II

Question 47

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

Answer 47

CLASS I

Question 48

MoI+ Mutation in Wilson disease

Answer 48

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

Question 49

CF of Wilson disease

Answer 49

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

Question 50

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

Answer 50

Low

Question 51

MoI + mutation of Hereditary Haemochromatosis

Answer 51

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

Question 52

CF of Haemochromatosis

Answer 52

1) Joint pain 2) skin pigmentation 3) Cardiomyopathy 4) DM | *liver **Cirrhosis** is a complication as the disease progresses

Question 53

LAb Diagnosis of Haemochromatosis?

Answer 53

elevated transferriniron saturation and ferritin concentration

Question 54

# 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

Answer 54

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

Question 55

MEN2A/B or both syndroms

Answer 55

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