6. Neurofibromatosis Type 1 and 2

Question 1

What is the clinical phenotype of NF1?

Answer 1

Neurocutaneous disorder with tumour predisposition

> 6 cafe-au-lait spots, neurofibromas, cognitive impairment, vision problems

Risk of malignant nerve sheath tumours and leukaemia

Question 2

What is the role of NF1?

Answer 2

TSG that negatively regulates RAS

NF1 mutations cause increased RAS activity –> increased signalling in MAPK pathway

Question 3

How is NF1 inherited?

Answer 3

AD

50% are de novo

Somatic (segmental) mosaicism common due to high mutation rate

Question 4

Why is RNA tested for NF1?

Answer 4

10% of variants affect splicing and are missed by conventional sequencing as they’re deeply intronic or misinterpreted by in silico predictions

Question 5

Why is tumour DNA tested alongside RNA in NF1?

Answer 5

Loss of the normal allele (LoH) is consistent with a pathogenic germline variant

Question 6

How is NF2 inherited?

Answer 6

AD

50% inherited, 50% de novo

Question 7

What is the clinical phenotype of NF2?

Answer 7

BIlateral vestibular schwannomas

Results in gradual hearing loss, balance problems

Question 8

How does the clinical phenotype of NF2 differ from NF1?

Answer 8

Fewer cafe-au-lait spots, later age of onset