Motor Neurone Disease
Gene: CYLD
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
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: LiteratureCreated: 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
Mode of pathogenicity
Other
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Frontotemporal dementia and/or amytrophic lateral sclerosis 8, MIM# 619132
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
Gene: cyld has been classified as Amber List (Moderate Evidence).
Gene: cyld has been classified as Amber List (Moderate Evidence).
Gene: cyld has been classified as Amber List (Moderate Evidence).
gene: CYLD was added gene: CYLD was added to Motor Neurone Disease. Sources: Literature Mode of inheritance for gene: CYLD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CYLD were set to 32666117; 32666099; 32185393 Phenotypes for gene: CYLD were set to Frontotemporal dementia and/or amytrophic lateral sclerosis 8, MIM# 619132 Mode of pathogenicity for gene: CYLD was set to Other Review for gene: CYLD was set to AMBER