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TAS Genetics ✅ > Autosomal Dominant Genetic Disorders ✅ > Flashcards

Autosomal Dominant Genetic Disorders ✅ Flashcards

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Biology 101 flashcards
1
Q

What are autosomal dominant disorders caused by?

A

‘Mono-allelic’ mutations affecting one copy (allele) of a gene on an autosomal chromosome, i.e. not X or Y

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2
Q

Which gender can be affected baby autosomal dominant disorders?

A

Both

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3
Q

How can autosomal dominant mutations. be inherited?

A

From affected parent, or occur de novo as a result of a new mutation

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4
Q

When are de novo mutations causing genetic disorders more common?

A

In severe disorders which prevent affected individuals having children

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5
Q

What is the risk of someone with an autosomal dominant disorder passing on the causative mutation to a child?

A

50%

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6
Q

What is the risk of parents having another affected child when a mutation has occurred de novo?

A

Around 1%

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7
Q

What does the 1% chance of parents having another child with a de novo mutation present?

A

The small risk of the presence of the mutation in mosaic form in one or other parent’s gonads (gonadal mosaicism)

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8
Q

What is mosaicism?

A

Presence of 2 or more genetically different cell lines that derive from the same zygote

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9
Q

How can the presentation of autosomal disorders vary?

A

Some autosomal disorders show incomplete penetrance, and many show variable expressivity

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10
Q

What is meant by incomplete penetrance?

A

Not all individuals who inherit a pathogenic mutation manifest with clinical features of the disorder

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11
Q

What is meant by variable expressivity?

A

Individuals who manifest with the condition show different severity of disease

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12
Q

Give 5 examples of autosomal dominant conditions

A
  • Marfan’s syndrome
  • Neurofibromatosis type 1 (NF1)
  • Tuberous sclerosis
  • Achondroplasia
  • Myotonic dystrophy
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13
Q

What is the incidence of Marfan’s syndrome?

A

1 in 5000

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14
Q

What is the genetic cause Marfan’s syndrome?

A

Monoallelic loss-of-function mutations in the FBN1 (fibrillin) gene, often inherited from an affected parent

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15
Q

What is being increasingly used in the diagnosis of Marfan’s syndrome?

A

FBN1 sequencing

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16
Q

What is FBN1 sequencing particularly useful for?

A

To guide advice to other family members who may be at risk of the disease

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17
Q

What is the incidence of neurofibromatosis type 1 (NF1)?

A

1 in 5000

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18
Q

What is the genetic cause of NF1?

A

Monoallelic loss-of-function mutations in NF1 gene, often inherited from an affected parent

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19
Q

What is increasingly being used to aid in the diagnosis of NF1?

A

NF1 sequencing and copy number analysis

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20
Q

What is NF1 sequencing and copy number analysis particularly useful for?

A

To guide advice to other family members who may be at risk of the disease

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21
Q

What does the clinical diagnosis of NF1 require?

A

The presence of 2 or more of the following:

  • 6 or more cafe at lait patches sized >15mm (or >5mm before puberty)
  • A plexiform neurofibroma, or 2 or more cutaneous neurofibromas
  • Axillary or inguinal freckling
  • Sphenoid wing dysplasia or long bone pseudoarthrosis
  • Optic nerve glioma
  • Two or more Lisch nodules (iris hamartomas)
  • A first degree relative with NF1
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22
Q
  • What are the other features of NF1?
A
  • Renal artery stenosis and scoliosis

- Malignant peripheral nerve sheath tumours

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23
Q

What % of individuals with NF1 develop malignant peripheral nerve sheath tumours?

A

10%

24
Q

What is the cognitive ability of individuals with NF1?

A

Most individuals have normal learning, but mild learning difficulties can be a feature

25
Q

What is recommended in the follow up of children with NF1?

A
  • Annual review by paediatrician

- Annual review by opthalmologist

26
Q

What is looked at in the annual review with a paediatrician in NF1?

A
  • Any unusual neurological symptoms
  • Growth
  • Development
  • Blood pressure
  • Scoliosis
27
Q

What is looked for in annual review with an ophthalmologist in NF1?

A

Optic glioma

28
Q

What is the incidence of tuberous sclerosis?

A

1 in 10,000

29
Q

What is the genetic cause of tuberous sclerosis?

A

Monoallelic loss of function mutations in the TSC1 or TSC2 gene

30
Q

What % of causes of tuberous sclerosis are caused by loss of function mutations in the TSC1 gene?

A

25%

31
Q

What % of cases of tuberous sclerosis are caused by loss of function mutations in the TSC2 gene?

A

60%

32
Q

In what % of cases of tuberous sclerosis is the causative gene unknown?

A

15%

33
Q

What proportion of mutations causing tuberous sclerosis occur de novo?

A

2/3

34
Q

What is sequencing and copy number analysis of TSC1 and TSC2 genes useful for in tuberous sclerosis?

A

To assist diagnosis in atypical cases and to allow accurate advice to families regarding risks of recurrence in future children and/or allow prenatal or pre-implantation genetic diagnosis

35
Q

How does the phenotype of tuberous sclerosis vary between individuals?

A

Some show only very subtle features, whereas others manifest early with severe neurological complications

36
Q

Why does the phenotype of tuberous sclerosis vary between individuals?

A

Because it shows highly variable expressivity

37
Q

What severe neurological complications may be present in tuberous sclerosis?

A
  • Infantile spasms
  • Severe developmental delay
  • Intractable seizures
38
Q

What causes the severe neurological complications of tuberous sclerosis?

A

CNS tubers

39
Q

What are the cutaneous manifestations of tuberous sclerosis?

A
  • Shagreen patches
  • Hypopigmented ‘ash leaf’ Macauley
  • Adenoma sebaceous
  • Periungal fibromas
40
Q

How common are cutaneous manifestations of tuberous sclerosis?

A

They are almost always present

41
Q

What can aid with the identification of hypopigmented patches?

A

UV Wood’s lamp (can be hard to see without)

42
Q

What prenatal presentation is strongly suggestive of tuberous sclerosis?

A

Prenatal presentation with multiple cardiac rhabdomyomas

43
Q

What usually happens in children that present prenatal with multiple cardiac rhabdomyomas with tuberous sclerosis?

A

They usually resolve post-Parton

44
Q

What are the other causes of morbidity and mortality in tuberous sclerosis?

A
  • Pulmonary complications

- Renal complications

45
Q

Give a pulmonary complication of tuberous sclerosis

A

Lymphangiomatosis

46
Q

Give a renal complication of tuberous sclerosis

A

Angiomyolipoma

47
Q

What is the incidence of achondroplasia?

A

1 in 27,000

48
Q

What is the genetic cause of achondroplasia?

A

A monoallelic gain-of-function mutation in the FGFR3 gene

49
Q

Are the mutations in achondroplasia inherited or de novo?

A

Can be either

50
Q

How can a diagnosis of achondroplasia be made?

A

On the basis of clinical features and skeletal survey, and confirmed by targeted sequencing for the common causative mutations

51
Q

What is the incidence of myotonic dystrophy?

A

1 in 8000

52
Q

What is the genetic cause of myotonic dystrophy?

A

Monoallelic triplet repeat expansion mutation in DMPK gene

53
Q

What is meant by myotonic dystrophy showing ‘anticipation’?

A

The disease is often more severe and younger onset with successive generations

54
Q

When is the greatest risk of expansion in myotonic dystrophy?

A

When the condition is passed from mother to child

55
Q

How is a diagnosis of myotonic dystrophy made?

A

Clinical, with EMG providing supportive evidence

56
Q

What can confirm the diagnosis of myotonic dystrophy?

A

Targeted genetic testing for an expansion of the DMPK gene

TAS Genetics ✅ (13 decks)

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