Submission Details

CYLD was first considered a causal gene for autosomal dominant frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis type 8 (ALS8) in 2020 following whole genome sequencing of two affected members and one unaffected member of a large family of European Australian decent. (Dobson-Stone et al., PMID: 32185393). CYLD codes for a deubiquitinating enzyme that specifically cleaves ‘Lys-63’-and linear ‘Met-1’ linked polyubiquitin chains and is involved in regulating NF-κB activation, Wnt signaling and TNF-alpha-induced necroptosis. CYLD has also been reported to cause a group of inherited skin adnexal tumor syndromes called CYLD cutaneous syndromes. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in molecular mechanism and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, autosomal dominant FTD and/or ALS8 (OMIM:619132) and autosomal dominant CYLD Cutaneous Syndromes: Brooke-Spiegler Syndrome (OMIM:605041), familial cylindromatosis (OMIM:132700), and multiple familial trichoepithelioma (OMIM:601606). The split curation for autosomal dominant Brooke-Spiegler Syndrome has been curated separately. Five missense variants that have been reported in five probands in two publications (PMIDs: 32185393 and 3468212) are included in this curation. Other missense variants reported in the literature have been excluded from scoring due to being outside the expert panel’s MAF cutoff (>0.00001) or not having an ALS phenotype (PMIDs: 36000313, 3468212, and 32666117). The mechanism of pathogenicity appears to be gain of function. This gene-disease association is also supported by experimental evidence; the preponderance coming from assays expressing the variant Met719Val (PMID: 32185393). Neuropathologic analysis of postmortem brain tissue of 2 affected individuals showed widespread glial CYLD immunoreactivity that was not present in other patients with sporadic FTD. There were also patchy areas of diffuse neuronal cytoplasmic CYLD staining in the hippocampus and frontal cortex, as well as CYLD immunoreactivity in the nuclei of pyknotic neurons. Transfection of primary mouse cortical neurons with mutant M719V CYLD resulted in an increased proportion of neurons with cytoplasmic TDP-43 staining (~55%) compared to cells transfected with wildtype CYLD (~34%). Co-transfection of flagged CYLD constructs followed by immunoprecipitation with anti-FLAG antibody reveals CYLD interacts with known ALS genes OPTN, TBK1 and SQSTM1, though M719V does not abrogate the interaction. Additional in vitro cellular studies show that the M719V mutation resulted in impaired autophagosome fusion with lysosomes compared to wildtype. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen ALS GCEP on February 23, 2023 (SOP Version 9).