Autosomal Dominant Genetic Disorders ✅ Flashcards
What are autosomal dominant disorders caused by?
‘Mono-allelic’ mutations affecting one copy (allele) of a gene on an autosomal chromosome, i.e. not X or Y
Which gender can be affected baby autosomal dominant disorders?
Both
How can autosomal dominant mutations. be inherited?
From affected parent, or occur de novo as a result of a new mutation
When are de novo mutations causing genetic disorders more common?
In severe disorders which prevent affected individuals having children
What is the risk of someone with an autosomal dominant disorder passing on the causative mutation to a child?
50%
What is the risk of parents having another affected child when a mutation has occurred de novo?
Around 1%
What does the 1% chance of parents having another child with a de novo mutation present?
The small risk of the presence of the mutation in mosaic form in one or other parent’s gonads (gonadal mosaicism)
What is mosaicism?
Presence of 2 or more genetically different cell lines that derive from the same zygote
How can the presentation of autosomal disorders vary?
Some autosomal disorders show incomplete penetrance, and many show variable expressivity
What is meant by incomplete penetrance?
Not all individuals who inherit a pathogenic mutation manifest with clinical features of the disorder
What is meant by variable expressivity?
Individuals who manifest with the condition show different severity of disease
Give 5 examples of autosomal dominant conditions
- Marfan’s syndrome
- Neurofibromatosis type 1 (NF1)
- Tuberous sclerosis
- Achondroplasia
- Myotonic dystrophy
What is the incidence of Marfan’s syndrome?
1 in 5000
What is the genetic cause Marfan’s syndrome?
Monoallelic loss-of-function mutations in the FBN1 (fibrillin) gene, often inherited from an affected parent
What is being increasingly used in the diagnosis of Marfan’s syndrome?
FBN1 sequencing
What is FBN1 sequencing particularly useful for?
To guide advice to other family members who may be at risk of the disease
What is the incidence of neurofibromatosis type 1 (NF1)?
1 in 5000
What is the genetic cause of NF1?
Monoallelic loss-of-function mutations in NF1 gene, often inherited from an affected parent
What is increasingly being used to aid in the diagnosis of NF1?
NF1 sequencing and copy number analysis
What is NF1 sequencing and copy number analysis particularly useful for?
To guide advice to other family members who may be at risk of the disease
What does the clinical diagnosis of NF1 require?
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
- What are the other features of NF1?
- Renal artery stenosis and scoliosis
- Malignant peripheral nerve sheath tumours
What % of individuals with NF1 develop malignant peripheral nerve sheath tumours?
10%
What is the cognitive ability of individuals with NF1?
Most individuals have normal learning, but mild learning difficulties can be a feature
