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lituranga t1_ja9kmon wrote

Reply to comment by jubears09 in Is there a genetic disease where the heterozygote has more severe disease symptoms than the homozygote? by Altranite-

That’s not true, there are many AR conditions with common pathogenic carrier mutations which mean that many affected individuals are absolutely homozygous without any consanguinity.

It’s not exceedingly improbable at all. Examples off top of my head are delta f 508 for Cystic fibrosis, all the ashkenazi Jewish common AR conditions, SMA, sickle cell disease, alpha thal, beta thal, and I’ve personally seen many patients with other disorders who are affected and homozygous for same pathogenic variant.

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jubears09 t1_ja9m58q wrote

Those are exceptions rather than the rule for rare disease. Ashkenazi Jews had a bottleneck effect; SSD is a gain of function, etc. They other thing they have in common is a relatively high allele frequency in the general population.

For interference where a heterozygote would be effected (and therefore selected again) most variants would be de novo; so a homozygous mutant would require simultaneous and identical de novo mutations to occur in the same individual.

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lituranga t1_ja9pb51 wrote

Yes fair, just meaning to clarify that the phrase exceedingly improbable is a bit inaccurate since there are a huge amount of examples of disorders that work this way in reality.

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