Clinical genetics - the basics

Question 1

Define multi-factorial/complex. Give an example.

Answer 1

The interaction of multiple genes (genetic predisposition) in combination with environmental factors e.g. TiiDM

Question 2

Define single gene genetic disorders. Give an example.

Answer 2

A mutation in a single gene. Shows Mendelian inheritance eg CF

Question 3

Define chromosomal genetic disease.

Answer 3

An imbalance or rearrangement in chromosome structure eg aneuploidy, deletion, translocation.

Question 4

Define mitochondrial genetic disease.

Answer 4

A mutation in mitochondrial DNA.

Question 5

What are somatic mutations?

Answer 5

Mutation(s) within a gene(s) in a defined population of cells that results in disease eg breast cancer.

Question 6

What are the features of autosomal dominant diseases?

Answer 6

50:50 chance of inheritance. Generally affect structural proteins, receptors, transcription factors eg Marfan’s, myotonic dystrophy, Huntington disease. Usually chromosome deletions or duplications.

Question 7

Define penetrance.

Answer 7

The frequency with which a specific genotype is expressed by those individuals that possess it, usually given as a percentage. E.g. Huntingtons is 100%, BRCA1 is 80%.

Question 8

Define expressivity.

Answer 8

Variation in expression - the extent to which a heritable trait is manifested by an individual.

Question 9

Define anticipation.

Answer 9

The symptoms of a genetic disorder become apparent at an earlier age as it is passed from one generation to the next. In most cases there is an increase in the severity of symptoms too.

Question 10

Define new dominant/de novo mutation.

Answer 10

A new mutation that has occurred during gametogenesis or in early embryonic development.

Question 11

What are the features of autosomal recessive diseases?

Answer 11

Seen in one generation. Parents usually unaware of carrier status. Gene mutations not chromosomes. Risk to offspring is 25% with two parent carriers.

Question 12

What are the features of X-linked disease?

Answer 12

Males affected. Females may be unaffected, mildly through to fully affected (eg fragile X). Males usually more severely affected than females. Can NOT have male to male transmission. Gene mutations and chromosome deletions/ duplications.

Question 13

What is Lyonisation?

Answer 13

X-inactivation. The process of random inactivation of one of the X chromosomes in cells with more than one X chromosome. Compensates for the presence of the double X gene dose. Most, but not all genes switched off on the inactivated X.

Question 14

What are the implications of Lyonisation in X-linked genetic disease?

Answer 14

• Approx. 50% of cells express the normal gene.
• Skewed X-inactivation - preference for ‘normal’ X chromosome to be inactivated - significant phenotype.
• Tissue variability – random preference for the X chromosome with the mutation to be active in crucial tissue group – eg muscle in Duchenne Muscular dystrophy

Question 15

What is an X-linked dominant condition?

Answer 15

Only one mutant gene required to cause disease so usually seen in females. E.g. Rett syndrome (lethal in males, phenotype only in females), fragile X syndrome

Question 16

What is an X-linked recessive condition?

Answer 16

Two mutant genes required. Rarely seen in females as affected male/carrier female parents would be required. E.g. red-green colour blindedness, haemophilia

Question 17

What are the features of mitochondrial inheritance?

Answer 17

Rare, males and females affected equally. Only 27 genes within mitochondrial DNA. Each cell has many mitochondria. Every mitochondrion has many copies of each gene. Mitochondria are inherited from the mother’s egg. An affected mother will give all her children the mutation. Highly variable expressivity and therefore severity of phenotype between relatives. All the children of an affected man will be unaffected