tag:blogger.com,1999:blog-1812431336777691886.post8883687641036180165..comments2024-02-29T03:57:00.088-05:00Comments on The Mermaid's Tale: Genes 'for' XLID -- the replication/falsifiability fallacyAnne Buchananhttp://www.blogger.com/profile/09212151396672651221noreply@blogger.comBlogger2125tag:blogger.com,1999:blog-1812431336777691886.post-49388080097516680052013-08-19T12:15:11.345-04:002013-08-19T12:15:11.345-04:00Thanks for the tempering comment, Kevin. You'...Thanks for the tempering comment, Kevin. You're absolutely right of course that there are unambiguous genes for some traits. But, it's a spectrum, from traits with definitively causal gene variants to polygenic traits to traits with multiple causal pathways and traits that require a triggering environment. Some variants have been relatively straightforward to determine, but we're left with a whole host of traits that have been stubbornly difficult to explain, and I think Piton et al. is a good reminder that it's too easy to assume causation. I think in part because genetics had such tremendous successes early on with 'simple' genetic traits that it's tempting to think that should still be the model going forward. Anne Buchananhttps://www.blogger.com/profile/09212151396672651221noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-60465588143562492132013-08-19T11:41:15.503-04:002013-08-19T11:41:15.503-04:00It is very true that genetic background will play ...It is very true that genetic background will play a big part in many so-called "Mendelian" disorders. However, this does not mean that we can never assign causality to any primary mutations. Even if the phenotypic manifestation is modified by other factors, in many cases it will be possible to say that one particular mutation is causal in the sense that if the person did not have that mutation they would most likely not have that condition. (As with a CFTR mutation in cystic fibrosis, for example). So, such a primary mutation may be necessary but not sufficient. Though it will certainly not provide a complete explanation for every aspect of a person's condition, it may be highly clinically relevant information. <br /><br />The results of Piton et al and Klassen et al are certainly salutary and many mutations previously classified as pathogenic may indeed have to be revisited as we learn more about the spectrum of genetic variation in the healthy population. In some cases, these will be simply false positives, while in others it may emerge that their penetrance is lower than previously thought (as they also show up in clinically unaffected people). On the other hand, the 80-90% of previously identified X-linked intellectual disability genes that DID pass their test as bona fide give a lot of confidence that assigning genetic causality in many cases is not a fool's errand.<br /><br /> Kevin Mitchellhttps://www.blogger.com/profile/07172255754953214162noreply@blogger.com