Motor Neurone Disease

Gene: CYLD

Red List (low evidence)

Limited gene-disease association classified by ClinGen

"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)."

Created: 8 Apr 2024, 6:39 a.m. | Last Modified: 8 Apr 2024, 6:39 a.m.

Panel Version: 1.8

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
frontotemporal dementia and/or amyotrophic lateral sclerosis 8 (MONDO:0030872)

Publications

• https://search.clinicalgenome.org/CCID:004615

I don't know

Original study (PMID: 32185393) identified a gain of function missense segregating 7 FTD cases (1 also with ALS) and 1 ALS case in an Australian family, that has a previously identified linkage peak in this region. Extensive genomic studies were conducted to exclude structural variation and repeats as causes. Supporting immunohistochemical evidence in brain tissue and extensive in vitro assays on the missense variant (M719V), showing a different mechanism of disease to loss of function that is associated with cutaneous phenotypes. Also, demonstrated a significant enrichment of rare missense variants in the deubiquitinase domain of CYLD (amino acids 593–948) in an FTD cohort, but not an ALS cohort. A subsequent Portuguese FTD study has identified two missense VUS in 2 FTD cases. Segregation studies or functional studies were not conducted (PMID: 32666117).
Sources: Literature

Created: 18 May 2021, 7:09 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Frontotemporal dementia and/or amytrophic lateral sclerosis 8, MIM# 619132

Publications

• 32666117
• 32666099
• 32185393

Mode of pathogenicity
Other

I don't know

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Frontotemporal dementia and/or amytrophic lateral sclerosis 8, MIM# 619132

Green List (high evidence)

Multiple reports of loss of function variants in patients with cutaneous phenotypes (OMIM).

Recent report of a missense variant segregating in 1 family with frontotemporal dementia and amyotrophic lateral sclerosis. Functional studies showed that the variant resulted in a gain of ubiquitinase function, opposite from the mechanism causing the well-documented cutaneous phenotypes (PMID: 32185393).

Created: 20 Apr 2020, 3:58 a.m. | Last Modified: 20 Apr 2020, 3:58 a.m.

Panel Version: 0.2372

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Brooke-Spiegler syndrome, 605041; Cylindromatosis, familial, 132700; Trichoepithelioma, multiple familial, 1, 601606; Frontotemporal dementia and amyotrophic lateral sclerosis

Publications

• 10835629
• 16307661
• 12950348
• 19807742
• 32185393