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
What is recommended in the follow up of children with NF1?
- Annual review by paediatrician
- Annual review by opthalmologist
What is looked at in the annual review with a paediatrician in NF1?
- Any unusual neurological symptoms
- Growth
- Development
- Blood pressure
- Scoliosis
What is looked for in annual review with an ophthalmologist in NF1?
Optic glioma
What is the incidence of tuberous sclerosis?
1 in 10,000
What is the genetic cause of tuberous sclerosis?
Monoallelic loss of function mutations in the TSC1 or TSC2 gene
What % of causes of tuberous sclerosis are caused by loss of function mutations in the TSC1 gene?
25%
What % of cases of tuberous sclerosis are caused by loss of function mutations in the TSC2 gene?
60%
In what % of cases of tuberous sclerosis is the causative gene unknown?
15%
What proportion of mutations causing tuberous sclerosis occur de novo?
2/3
What is sequencing and copy number analysis of TSC1 and TSC2 genes useful for in tuberous sclerosis?
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
How does the phenotype of tuberous sclerosis vary between individuals?
Some show only very subtle features, whereas others manifest early with severe neurological complications
Why does the phenotype of tuberous sclerosis vary between individuals?
Because it shows highly variable expressivity
What severe neurological complications may be present in tuberous sclerosis?
- Infantile spasms
- Severe developmental delay
- Intractable seizures
What causes the severe neurological complications of tuberous sclerosis?
CNS tubers
What are the cutaneous manifestations of tuberous sclerosis?
- Shagreen patches
- Hypopigmented ‘ash leaf’ Macauley
- Adenoma sebaceous
- Periungal fibromas
How common are cutaneous manifestations of tuberous sclerosis?
They are almost always present
What can aid with the identification of hypopigmented patches?
UV Wood’s lamp (can be hard to see without)
What prenatal presentation is strongly suggestive of tuberous sclerosis?
Prenatal presentation with multiple cardiac rhabdomyomas
What usually happens in children that present prenatal with multiple cardiac rhabdomyomas with tuberous sclerosis?
They usually resolve post-Parton
What are the other causes of morbidity and mortality in tuberous sclerosis?
- Pulmonary complications
- Renal complications
Give a pulmonary complication of tuberous sclerosis
Lymphangiomatosis
Give a renal complication of tuberous sclerosis
Angiomyolipoma
What is the incidence of achondroplasia?
1 in 27,000
What is the genetic cause of achondroplasia?
A monoallelic gain-of-function mutation in the FGFR3 gene
Are the mutations in achondroplasia inherited or de novo?
Can be either
How can a diagnosis of achondroplasia be made?
On the basis of clinical features and skeletal survey, and confirmed by targeted sequencing for the common causative mutations
What is the incidence of myotonic dystrophy?
1 in 8000
What is the genetic cause of myotonic dystrophy?
Monoallelic triplet repeat expansion mutation in DMPK gene
What is meant by myotonic dystrophy showing ‘anticipation’?
The disease is often more severe and younger onset with successive generations
When is the greatest risk of expansion in myotonic dystrophy?
When the condition is passed from mother to child
How is a diagnosis of myotonic dystrophy made?
Clinical, with EMG providing supportive evidence
What can confirm the diagnosis of myotonic dystrophy?
Targeted genetic testing for an expansion of the DMPK gene
