Asking for papers: rare variants of potentially moderate impact
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Entering edit mode
10 weeks ago

Hi, I don't know where and in which form to ask this question, I try here...

We know that some very rare variants may cause rare disease. They are rare, their effect is huge.

We know that common variants may be associated with the disease. They are common, their effect is minuscule by themself, but in combination they comprise Genomic Risk Scores and can lead to substantial variation in common disease incidence.

We know that genomic risk scores explain only part of the total hereditability.

We know that around 70 SNVs/indels per generation occur de novo, 1-2 of them in coding parts. If we take one family of normal (mostly healthy) people, we can observe quite a bit of private ultra-rare variants of unknown significance. However actually such variants can be functional and can make a little-to-middle effect on the disease susceptibility, but they are not covered in neither rare disease nor complex phenotype studies.

Is there research on such variants? What is the name for such variants? Could you share any papers covering this topic?

(I am not that unfamiliar with the topic, there were some research based on RVAS methods that identify genes in cases frequently affected by moderate impact variants - but I'd be glad if you share more and modern papers on this. In a perfect world any such variant could be checked in a model organism, if it modifies the function of the protein somehow, e.g. decreses some ion channel activity by 20% - but can it be done in a systematic way on a per patient basis with at least some degree of confidence?)

The wiki page ( https://en.wikipedia.org/wiki/Missing_heritability_problem ) does not have what I am asking about listed, namely - rare little/moderate effect variant that affect disease predisposition, summing up to polygenic background.

human disease genetics • 235 views
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Entering edit mode
10 weeks ago

Here is a blog devoted to disseminating information on rare genetic diseases in children:

http://kidsgenomics.org/

KidsGenomics will instead focus on genetic diseases that affect children, including rare inherited disorders and pediatric cancers.

PS: I changed the type to question,

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Entering edit mode

It looks great and partially addresses the variable phenotype question, thank you!

(I'd wish the author post more frequent since (s)he obviously is talented in this, but I believe it is a very busy person...)

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