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L3 Clinical Genomics > Osteogenesis imperfecta > Flashcards

Osteogenesis imperfecta Flashcards

1
Q

What 3 components make up connective tissues?

A
  • Fibres
  • Ground substance
  • Cells
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2
Q

What is ground substance?

A

Gel-like substance in the extracellular space containing all components of the extracellular matrix except for fibrous material e.g. collagen and elastins

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3
Q

What are the cells of connective tissue? (5)

A
  • Fibroblasts
  • Adipocytes
  • Macrophages
  • Mast cells
  • Leucocytes
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4
Q

What are the fibres of connective tissue? (2)

A
  • Collagen
  • Elastins
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5
Q

What is the function of connective tissue? (3)

A
  • Acts as a cellular glue
  • Supports and connects internal organs
  • Forms bones, walls of blood vessels, gives skin elasticity, attaches muscle to bone, protects the organs
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6
Q

What are examples of genetic connective tissue disorders? (3)

A
  • Osteogenesis imperfecta
  • Ehlers Danlos syndrome
  • Marfan syndrome
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7
Q

What are examples of autoimmune connective tissue disorders? (2)

A
  • Lupus
  • Scleroderma
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8
Q

What are sarcomas?

A

Cancers that arise in connective tissues

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9
Q

What is osteogenesis imperfecta? (2)

A
  • Collective term for a heterogeneous group of connective tissue syndromes characterised by liability to fractures throughout life
  • Commonly caused by defects in collagen
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10
Q

What is the incidence of osteogenesis imperfecta?

A

1 in 20 000 births

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11
Q

What are the clinical features of osteogenesis imperfecta? (7)

A
  • Bone fractures with little trauma (brittle bones)
  • Loose joints
  • Weak teeth (dentinogenesis imperfecta)
  • Blue sclera
  • Bowed legs and arms
  • Short stature
  • Hearing loss
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12
Q

What type of genetic testing is required for an OI referral? (2)

A
  • Targeted NGS for OI genes, don’t need whole genome sequencing
  • There are 30+ genes associated with OI so Sanger is too long, expensive and labour intensive
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13
Q

What is the main genetic cause of OI? (3)

A
  • 90% variants are in COL1A1 and COL1A2 collagen genes and are dominant
  • There are autosomal recessive genes e.g. BMP1 and X-linked genes e.g. PLS3
  • All genes causing OI cause collagen defects
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14
Q

What are the features of collagen? (4)

A
  • Can undergo biomineralisation to stiffen tissues
  • Produced by osteoblasts and fibroblasts
  • Fibrous protein which forms part of the extracellular
  • Most abundant protein in humans
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15
Q

What are the types of OI associated with COL1A1 and COL1A2? (4)

A
  • Type 1: classic
  • Type 2: lethal
  • Type 3: progressively deforming
  • Type 4: common variable OI with normal sclerae
    (All autosomal dominant)
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16
Q

What are the features of type 1 OI? (9)

A
  • Classic
  • Mild
  • Fractures
  • Normal stature
  • Little or no deformity
  • Blue sclera
  • 50% have hearing loss
  • Joint hypermobility
  • No dentinogenesis imperfecta
17
Q

What are the features of type 2 OI? (5)

A
  • Lethal in pregnancy
  • Multiple fractures
  • Unmineralised bones
  • Beaded ribs (rib cage collapses and damages internal organs)
  • Short/bowed long bones
18
Q

What are the features of type 3 OI? (9)

A
  • Progressively deforming
  • Severe but non-lethal
  • Apparent at birth
  • Multiple fractures
  • Bone deformity
  • Grey/white sclera
  • Short stature
  • Wheelchair bound
  • Dentinogenesis imperfecta
19
Q

What are the features of type 4 OI? (7)

A
  • Common variable OI with normal sclerae
  • Moderate severity
  • Fractures
  • Normal to grey sclera
  • Variable short stature
  • Dentinogenesis imperfecta
  • Adult onset hearing loss
20
Q

What is OI type 5? (3)

A
  • Caused by a single variant c.-14C>T in IFITM5 gene
  • Variant is in the 5’ non coding DNA before the first exon and interferes with correct transcription
  • Autosomal dominant inheritance
21
Q

Why is NGS analysis of many genes necessary?

A

Many genes can be involved in causing one type of disorder

22
Q

Which type of OI do you expect to see in children?

A

Type 3 (quite severe)

23
Q

How do you go about a referral for OI genetic testing? (2)

A
  • Targeted NGS to identify variants
  • Variant analysis to classify variant
24
Q

What is the structure of collagen genes? (5)

A
  • Each gene consists of approximately 50 exons
  • Each exon codes for approximately 20 amino acids
  • Each exon begins and ends on a complete triplet codon
  • N and C terminal exons encode the N and C terminal propeptide regions which are important for processing and formation of collagen fibrils
  • Triplet repeat in about 40/50 exons with a glycine in every third position (Gly-X-Y repeat)
25
Q

What is the role of glycine in collagen? (5)

A
  • Helix is formed by intertwining 3 collagen COL1A chains (2xCOL1A1, 1xCOL1A2)
  • Vital for the structural integrity of the repeating helix
  • Every third amino acid is the centre of the helix (Glycine)
  • Glycine is the smallest amino acid so the only one that can be here and maintain the helix
  • Any swap disrupts the helix structure
26
Q

What are qualitative COL1 defects? (2)

A
  • Where mutations result in the synthesis of a structurally abnormal alpha collagen that then tries to form a helix with structurally normal alpha collagens (e.g. missense)
  • Causes disturbed helical folding so can’t function properly
27
Q

Which types of OI are caused by qualitative defects?

A

Types 2 and 4

28
Q

What are quantitative COL1 defects? (2)

A
  • Mutations that lead to premature truncation (nonsense, frameshifts, targeted by NMD) resulting in a reduction in the amount of collagen
  • The remaining WT collagen is fine but the reduction is enough to cause the phenotype
29
Q

Which types of OI are caused by quantitative defects?

A

Mostly type 1 (milder)

30
Q

What are the benefits of doing familial testing? (2)

A
  • Members with the variant can start treatment early, make informed lifestyle choices, have prenatal testing for future offspring
  • Members without the variant can get reassurance that they don’t have it and can’t pass it on
31
Q

What is the treatment for OI? (2)

A
  • Bisphosphonates to attempt to increase bone density
  • No cure

L3 Clinical Genomics (14 decks)

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