Here is a taste of the skepticism:
I have shared the paper with a couple of top notch human geneticists - who, in turn, thought that the paper was a bit of a joke. As one pointed out, if this was the profoundly important finding that NEJM's editorial claimed it to be, then publishing it in NEJM would be akin to Watson and Crick publishing their 1953 paper in Popular Mechanics rather than Nature!And another comment on the stats:
I believe at least one of these individuals is preparing a formal critique for publication. However, he has already flagged a number of problematic issues, including the Figure 1 data, the large number of unattached technical labels, and the failure to report whether those with the mutation suffered from other far more serious conditions (a likely result of lysosomal enzyme disease is developmental regression). As we know, Down's Syndrome patients have been reported to have an abnormally high incidence of stuttering, but their speech disorder is a relatively minor part of their condition. And, of course, not all persons who stutter have Down's Syndrome. You suggest that what Kang et al. might have found is a sub-type of the stuttering population (maybe,
like those with Down's Syndrome?), but that is NOT what they claimed in their paper. Anyhow, let's wait to see how this plays out when others with more expertise than me formerly comment on this paper.
By coincidence, a few days ago Nature carried the attached paper describing the unraveling of the Zebra Finch genome. They observed that more than 800 genes were functionally associated with the production of the Zebra Finch's learned song. And we're supposed to believe that one mutation in one chromosome site is functionally related to stuttering?
Regarding the 6%: The BRCA-1 mutation accounts for about 5% of breast cancer cases. We already know that stuttering is not a simple Mendelian trait with a single locus controlling expression. I would expect to find many loci, each representing independent paths to produce the same phenotype.
Regarding the Chi Square test: there are two problems in the figure. First, some subjects with the normal genotype are stutterers. Second, not all carrying the mutations are stutterers.The text asserts that the former individuals get their stuttering from another source. In the latter case, not all carriers need express the phenotype. From twin studies, we know that penetrance in stuttering is not 100% That is, not all individuals carrying the same genotype will express the same phenotype. This is going to confound the Chi Square test, which is a measure of how well phenotypes match genotypes. This will probably always be true in such studies of stuttering inheritance. Non-genetic effects - including fetal and juvenile brain development - may play a part in phenotypic expression. Social conditions may also play a part.
One could argue that such explanations are speculative excuse-making. They are speculative, but I think they are reasonable. The numbers are shaky, but that's the nature of inheritance outside of Biology 101 laboratory assignments. I still need to see some biology to make sense of the connection between the lysosomal proteins and speech, but that's another matter.
I am also a bit concerned. They did this Chi Square test which didn't turn out to be remarkable, but then they found a very good correspondence between a mutation in the lysosomal genes and stuttering (except for one female). I am not sure how this last observation can be included in a Chi Square test to prove that the statistical significance has increased to a discovery beyond doubt.
We need one or two other genetics team to have a true debate on this result. And we should always remember that the results significantly depend on the reliability of the lead on-hands scientist which I believe is Kang. If he has messed up, unwillingly or knowingly, we will be chasing a phantom.