Revision of the basic concepts in hereditary disease

Monogenic vs polygenic inheritance

• Monogenic: single gene aetiology
  • 6 patterns of inheritance - AD, AR, AXL, Y-linked, mitochondrial
  • Historically identified through study of families ('linkage')
  • Mendelian disease
• Polygenetic: multiple genes
  • Often environmental factors contribute as well as genetics
  • Evaluated by looking at large populations (GWAS)

Genetic abnormalities leading to monogenetic disease

• Single nucleotide variants (SNVS) result in several types of protein change: missense (e.g. substitution), nonsense (e.g. generation of stop codon) or splice site alteration
• Small insertions and deletions (incels) result in either:
  • In-frame indels: result in gain or losses of amino acids, amino acid substitutions or generation of premature top codons or defects in splicing
  • Out-of frame indels: typically result in franshift changes that requently result in premature trunkation of the encoded protein
• Loss of function (LOF) mutations typically result from nonsense, frameshirt or splice site mutations

Approaches to genetic testing for monogenetic disease

• Testing for a single gene - 'first' generation (Sanger) sequencing
• Next generation sequencing for diseases with genetic heterogeneity - disease-targeted gene panel, whole-exome sequencing, whole-genome sequencing

Genetic endocrine diseases

Identifying patients with a hereditary endocrine disease

• Must consider the possibility of genetic disease in a broad range of clinical presentations (e.g. many of the endocrine tumours)
• Careful history, in particular FHx
• Careful examination for subtle specific features of a disorder
• Common features:
  • Young age of onset
  • Tumour multiplicity (affecting either the same or different tissues)
  • Positive FHx
  • Pathognomonic clinical features (i.e. specific clinical conditions)

Example of monogenetic endocrine syndromes

• MEN type 1 and 2
• Von Hippel-Lindau