Endocrine Genetics

Question 1

Monogenic vs polygenic Inheritance

Answer 1

Monogenic disorders
→ Single gene aetiology
→ 6 patterns of inheritance
→ AD, AR, XLD, XLR, Y-linked, mitochondrial
→ Historically identified through study of families (‘linkage’)
Polygenic disorders
→ Multiple genes
→ Often environmental influences
→ Evaluated by looking at large populations (GWAS studies

Question 2

Genetic abnormalities leading to monogenic disease?

Answer 2

Majority of genetic abnormalities associated with monogenic disease are either single
nucleotide variants (SNVs) or small insertions or deletions (indels)
Single nucleotide variants (SNVs) result in several types of protein coding change:
* Missense amino acid change (i.e. substitution of one amino acid with another)
* Nonsense amino acid change (i.e. generation of a stop codon)
* Splice site alteration (e.g. defective splicing from change to donor or acceptor splice site)
Small insertions and deletions (Indels) result in either:
In-frame indels: result in gains or losses of amino acids, amino acid substitutions or generation of
premature stop codons or defects in splicing
Out-of frame indels: typically result in frameshift changes that frequently result in premature
truncation of the encoded protein
Loss of Function (LOF) mutations typically result from nonsense, frameshift or canonical
splice site mutations

Question 3

The benfits of genetic testing?

Answer 3

Benefits for the Patient
* Allow appropriate investigation and treatment of disease
* Ability to undertake screening for clinical features that may not be apparent
* Prognostic information regarding disease course
Benefits for first degree relatives and/or progeny
* Identify first degree family members who may be at risk of disease
* Identify family members who do not harbor the genetic change
* Where appropriate, to enable pre-conception genetic counseling/pre-natal diagnosis
**Academic / Research benefits **
Potential Future Clinical Benefits
* Advent of personalized medicine – matching therapies to genetic defect

Question 4

Pre-genetic test: clinical evaluation

Answer 4

• Early disease onset (childhood)
• Relevant FH
• Specific disorder

Question 5

Genetic testing workflow:diagnostic testing?

Answer 5

add the photo from mobile

Question 6

Two main Monogenic endocrine tumor syndromes?

Answer 6

• Multiple Endocrine Neoplasia Type
  1 (MEN1)
• Multiple Endocrine Neoplasia Type
  2 (MEN2A)

Question 7

About MEN 1?

Answer 7

• Rare hereditary endocrine cancer syndrome characterised primarily by tumours of 3 Ps: Parathyroid, Pituitary and entroPancreatic.
• Autosomal Dominant
• Classic tumour suppressor in endocrine tissue
• Mutation is on 11q13
• Mutation causes loss/reduced protein function