. Rare Variant Burden Analysis within Enhancers Identifies CAV1 as an ALS Risk Gene. Cell Rep. 2020 Dec 1;33(9):108456. PubMed.


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  1. On the CAV1 paper, I think this is very interesting work exploiting the power of WGS and the freedom of information/data offered through the ProjectMINE initiative, which is arguably the single most important advance in the ALS-FTD since the identification of C9ORF72 mutations.

    That noncoding variants contribute to ALS-FTD is not surprising, but by focusing on enhancers they have isolated a credible gene in CAV1, which has already been linked to neurodegeneration. I think variants in UTRs and promoters that influence the expression level of other genes linked with ALS will be found to play a role in ALS-FTD.

    On the HTT paper, the possibility of a link between HTT and ALS-FTD is intriguing given the clear links to other expansions in ATXN2 and C9ORF72. However, in this study, while they did find HTT expansions in patients, these were very rare, and the longest expansion was associated with a very atypical case, a 17-year-old who did not have FTD but actually the Westphal variant of HD.

    Despite this, the patient continues to be included in their categorization as an FTD case in tables 1 and 2. The pathological data excluded huntingtin inclusions in the spinal cord but did intriguingly find inclusions in the prefrontal cortex. It was not clear how abundant these were and it remains unclear if HTT expansions are mechanistically involved in disease causation.

    Nonetheless, it remains possible that cellular stresses invoked by an HTT expansion could contribute an additional “hit” to a cell that could act with other environmental/genetic factors and lead to ALS-FTD. This is further evidence of the value and the potential complexities that arise from WGS.

    View all comments by Jemeen Sreedharan

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  1. Huntingtin Repeats Cause—FTD, Caveolin Variants—ALS?