Mutation and inheritance revision

Types of mutation

• Stop (nonsense) mutation: mutated codon is a premature stop codon
• Missense mutation: mutated codon codes for a different amino acid
• Silent mutation: mutated codon codes for the same amino acid
• Frameshift mutations: occur when the addition (insertion) or removal (deletion) of a base alters the reading frame of the gene
• Triplet expansion: triplet is repeated

Modes of inheritance

• Autosomal dominant: only one copy of a disease allele is necessary for an individual to be susceptible to expressing the phenotype
  • Disease seen in all generations
  • 50% risk of affected child if parent is affected
• Autosomal recessive: two copies of a disease allele are required for an individual to be susceptible to expressing the phenotype
  • Often only one generation affected
  • 1 in 4 risk of an affected child if parents are carriers
  • Increased likelihood in consanguineous families
• X-linked dominant: only one copy of a disease allele on the X chromosome is required for an individual to be susceptible to an X-linked dominant disease, males and females can be affected but males more severely affected as they only have one X chromosome
  • Risk of child being affected is 1 in 4
  • If you know it is male - 1 in 2
• X-linked recessive: two copies of a disease allele on the X chromosome are required for an individual with two X chromosomes (a female) to be affected with an X-linked recessive disease
• De-novo dominant: occurs when a de-novo variant in one copy of a gene is sufficient to result in a clinical phenotype
  • A significant proportion of severe neonatal presentations are de-novo genetic
• Penetrance: how likely you are to have the disease if you have the genetic mutation
  • For a disease to be considered one that has mendelian inheritance (autosomal dominant, autosomal recessive, X-linked), it has to have high penetrance
• Multifactoral inheritance: lots of little variations contribute to the disease in the same way as environmental risk factors
  • The variants can be described as ‘low penetrance’

Methods of genetic testing

What makes a useful genetic test?

• Predictive of disease
• Contribute to security of diagnosis
• Indicate treatment/affect management