Retinoblastoma and Incomplete Penetrance

[MudPhud20XX]

So the way Kaplan Medical Genetics explains "Incomplete Penetrance" is using Retinoblastoma(Rb), which Kaplan categorized as autosomal dominant dz.

Kaplan says 10% of individuals who inherit Rb mutation doesn't get additional somatic mutation in the normal copy and thus Rb does not develop. Therefore, the penetrance of Rb is 90%.

I feel like this 90% chance is pretty high. I mean we have extremely sophisticated proofreading machinaries and having one copy of mutant Rb I don't think affects the cell's ability to proofread. What do you guys think?

I also have some additional questions:

1. So pretty much all the tumor suppressor gene related genetic disorders should stick to the autosomal dominant pattern, correct? What other types of genetic disorders (not the tumor suppressor related dz) would be examples of incomplete penetrance?

2. The part I am not really confident is that the fact that a person inherit mutant Rb mutation does not really do anything. It is not the autosomal dominant pattern we've known in classic Mendelian genetics. So can you really say Rb is an autosomal dominant disease or should I say Rb follows the pattern of autosomal dominant disease.

Many thanks in advance.

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[Myxedema]

By definition, "autosomal dominant" should mean if you have the "gene" (genotype), you must also have the "disease" (phenotype). However, that is not always the case:
- Has the gene (+genotype), no signs/symptoms (-phenotype): Incomplete penetrance
- Has the gene (+genotype), shows less severe signs/symptoms (~phenotype): Variable expression
"Penetrance" is the probability a person with the genotype will show the phenotype. If the penetrance of retinoblastoma of 90%, then it means 90% of individuals carrying the mutation will express the trait. Note that it says nothing about the severity; that is about variable expression.

1. So pretty much all the tumor suppressor gene related genetic disorders should stick to the autosomal dominant pattern, correct? What other types of genetic disorders (not the tumor suppressor related dz) would be examples of incomplete penetrance?

Yes; and hypertrophic cardiomyopathy is typically autosomal dominant with incomplete penetrance.

2. The part I am not really confident is that the fact that a person inherit mutant Rb mutation does not really do anything. It is not the autosomal dominant pattern we've known in classic Mendelian genetics. So can you really say Rb is an autosomal dominant disease or should I say Rb follows the pattern of autosomal dominant disease.

"Follows pattern of autosomal dominant" = "is autosomal dominant". You're right that incomplete penetrance goes against the definition of "dominant", but unfortunately, medicine is riddled with exceptions to the rules, and this is one of them.

 

[ulikedaggers]

Rb is a tumor suppressor. In the case of tumor suppressors, the diseased-state is "more likely to develop cancer" not "will have cancer".

 

[ChessMaster3000]

By definition, "autosomal dominant" should mean if you have the "gene" (genotype), you must also have the "disease" (phenotype). However, that is not always the case:
- Has the gene (+genotype), no signs/symptoms (-phenotype): Incomplete penetrance
- Has the gene (+genotype), shows less severe signs/symptoms (~phenotype): Variable expression
"Penetrance" is the probability a person with the genotype will show the phenotype. If the penetrance of retinoblastoma of 90%, then it means 90% of individuals carrying the mutation will express the trait. Note that it says nothing about the severity; that is about variable expression.

Yes; and hypertrophic cardiomyopathy is typically autosomal dominant with incomplete penetrance.

"Follows pattern of autosomal dominant" = "is autosomal dominant". You're right that incomplete penetrance goes against the definition of "dominant", but unfortunately, medicine is riddled with exceptions to the rules, and this is one of them.

Are oncogene mediated cancers not considered autosomal dominant?

 

[Myxedema]

Are oncogene mediated cancers not considered autosomal dominant?

There's a nuance between cancers and cancer syndromes. For instance, many different types of cancer will show p53 mutations, but germline inactivation of p53 results in Li-Fraumeni syndrome. Neoplasia seen in either type would be "tumor suppressor gene mediated". The most common types of cancer syndromes, familial retinoblastoma, Li-Fraumeni syndrome and HNPCC, are all autosomal dominant.