Why is the mechanism of inheritance for this disease autosomal dominant?

Question

An unrelated couple has a daughter and a son with the same rare condition. Neither parent has any obvious signs of the condition, but the father's mother (paternal grandmother) and her brother have the same condition. Select the most likely mode of inheritance:

• A. X-Linked
• B. Autosomal recessive
• C. Autosomal dominant
• D. Multifactorial
• E. Mitochondria

The correct answer is C. But I'm confused why it would be autosomal dominant when neither parent has the phenotype. I thought it might be autosomal recessive, even though this mode usually does not have a family history, just because of the fact that the paternal grandmother and her brother both had the disease, and this is consistent with the horizontal pattern associated with autosomal recessive inheritance. For it to be autosomal dominant, the disease would have to be incompletely penetrant, which seems like a less likely scenario than it being autosomal recessive.

Can someone explain why it is dominant, not recessive?

Thanks!

Answer 1

I think this question is not possible to answer without knowing the frequency of the deleterious alleles in the population. There's no way to assess whether incomplete penetrance is more or less likely than an undetected mutation in the mother's side. Since the question doesn't mention the mother's family at all, and only the father's, that suggests to me that the question writers don't want you to think that anything is wrong in the mother's side. That would make it dominant with incomplete penetrance.

Answer 2

Possible answers

A. X-Linked

It is possible. However, it is unlikely. The condition is claimed to be rare and as the daughter carries it, it means that the mother must have been a carrier. As the paternal grandmother also express the condition, it means both of her parents must have been carrying it. It is therefore a little unlikely. We would mainly see the condition in men but much fewer cases in women.

B. Autosomal recessive

It is indeed possible. As A, it is unlikely though. As the condition is rare, it is unlikely that both the parents of the paternal grandmother were both carrying the mutant allele and also the mother of the two kids is carrying the mutant allele. I would tend to think it is therefore unlikely. If we had more information (such as the frequency of the disease and/or how many siblings bother the paternal grandmother has), then we could have a better opinion about the likelihood of "B." being the good answer.

C. Autosomal dominant

No, it can't be as none of the parents don't express the condition

D. Multifactorial

The term "multifactorial" is a little unclear to me. It might mean that there is environmental variance and/or it might mean that there are several loci that affect the inheritance of this condition (with eventually some epistasis). All of these are definitely possible and likely (see below).

E. Mitochondria

It is unlikely as 1) the disease is rare and 2) the father's mother expressed the disease. The father did not transmit the mtDNA (as mtDNA is inherited from the mother only).

What I would answer

For the vast majority of phenotypic conditions we consider, the inheritance is controlled by several SNPs and there is some non-zero environmental variance (that is, heritability is different from 1; see this post).

In my opinion, the question is hard to answer, not because it is a hard question but because it lacks information (and clarity). If I really had to answer, I would probably answer "multifactorial".

Answer 3

Autosomal Dominant with incomplete penetrance can be fairly common, for example

SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT; SPG3A

HYPOPHOSPHATEMIC RICKETS, AUTOSOMAL DOMINANT; ADHR

There's also the chance of mosaicism in the father. Check OMIM for incomplete penetrance and autosomal dominant to get an idea.