- Factors affecting gene expression (in AD disorders)

Factors affecting gene expression

 

 (in Autosomal dominant disorders)

1.     Pleiotropy

2.     Variable expressivity

3.     Reduced penetrance

4.     New mutations

5.     Homozygosity

6.     Knudson two-hit hypothesis

Pleiotropy

·        A single gene (AD) that may give rise to ≥ 2 apparently unrelated effects.

·        In tuberous scelerosis, some affected individuals may have all features (learning difficulties, epilepsy, facial rashes,…)

·        Pleiotropy can result from different mutations in the same gene

·        AD traits may involve only one organ of the body i.e. the eye in congenital cataract. 

Variable expressivity  

·        Striking variation in the clinical features of AD disordes from person to person , even in the same family.

·        In AD polycystic kidney disease, some affected individuals develop renal failure in early adulthood whilst others have just a few renal cysts without affection of renal function.

Reduced Penetrance

·        Penetrance describes the frequency with which phenotypic manifestation of a gene are expressed.

·        A highly penetrant gene (100% penetrance) will express itself almost regardless of the effect of the environment or other interacting gene.

·        This phenomenon explains apparent skipped generations in certain pedigrees.

·        Reduced penetrance when the gene produces characteristic features much less often.

Factors Affecting Penetrance:

1.     Modifier genes.

2.     Hormonal/ reproductive factors.

3.     Response to DNA damage.

4.     Carcinogens (Not everyone with an altered gene develops cancer).

New mutations

·        AD disorders sometimes appear in a child of unaffected parents It may be due to:

o   a spontanous mutation in one of the gametes leading to

the conception of the affected person. This is the

most common reason for absence of a family

history in dominant disorders

o   Advanced paternal age.

o   parental mosaicism – very occasionally a healthy parent harbours the mutation only in some of their cells, e.g. in their gonads. This can account for recurrences of autosomal dominant disorders in siblings born to apparently unaffected parents. It has been described in congenital lethal osteogenesis imperfecta

o   non-paternity – if the apparent father is not the biological father.

·        About 80% of patients with achondroplasia have experienced a mutation in (FGFR3) gene

Homozygosity

In the rare situation where both parents are affected by the same autosomal dominant disorder, there is a 25% risk that a child will be homozygous for the altered gene.

This usually causes a more severe phenotype, which may be lethal, as with achondroplasia.

Knudson two-hit hypothesis

Some autosomal dominant conditions related to cancer susceptibility follow Knudson two-hit hypothesis.

Is the hypothesis that cancer is the result of accumulated mutations to a cell's DNA.

An example is mutation in the retinoblastoma (Rb) gene. If a child inherits the susceptibility, i.e. a mutation in one copy of the Rb gene, then a

tumour will occur if a second hit occurs on the working copy in a cell of the relevant type, so that the child inheriting a mutation will often have a tumour in both eyes, but approximately 10% will escape with neither

eye affected.

To illustrate the differences between penetrance and expressivity: 

·     Consider the condition neurofibromatosis type 1 (NFI).

·     NFI is an AD disorder cause by mutation in NFI gene (17 p11.2)

·     NFI characterized by: café au lait spots, neurofibromas, Lisch nodules, optic glioma and skeletal manifestations.

·     Although 100% penetrant, NFI has marked variability in expression, some affected individuals have only cafe` au lait spots, whereas others in the same family may experience life-threatening complications. 

Reduced penetrance and variable expressivity together with the pleiotropic effects of a mutent allele , all need to be taken into account when providing genetic counseling to individuals at risk for autosomal dominantly inherited disorders.