Abstract
Background: CYLD Lysine 63 Deubiquitinase gene (CYLD) was recently identified to be a novel causative gene for frontal temporal dementia (FTD)-amyotrophic lateral sclerosis (ALS). In the current study, we aimed to (1) systematically screen the mutations of CYLD in a large cohort of Chinese ALS patients, (2) study the genotype–phenotype correlation, and (3) explore the role of CYLD in ALS via rare variants burden analysis. Methods: A total of 978 Chinese sporadic ALS (sALS) patients and 46 familial ALS (fALS) patients were sequenced with whole-exome sequencing and analyzed rare variants in CYLD with minor allele frequency <0.1%. Results: In total, seven rare missense variants in CYLD have been identified in 7 (0.72%) patients among 978 sALS patients. Two (4.3%) rare missense variants were identified among the 46 fALS cases, in which one patient was diagnosed as having comorbidity of ALS and progressive supranuclear palsy (PSP). Moreover, the burden analysis indicated no enrichment of rare variants in CYLD among patients with ALS. Conclusion: In conclusion, our study extended the genotype and phenotype of CYLD in ALS, but the pathogenicity of these variants needs to be further verified. Moreover, burden analysis argued against the role of CYLD in the pathogenesis of ALS. More studies from different ethnicities would be needed.
Highlights
A heterozygous missense variant in CYLD Lysine 63 Deubiquitinase gene (CYLD) was found to co-segregate with the frontal temporal dementia (FTD)-amyotrophic lateral sclerosis (ALS) in an autosomal dominant inherited European Australian family (Dobson-stone et al, 2020)
No variant was found in the deubiquitinase domain of CYLD, which was revealed to have a significant enrichment in FTD cases by the previous study (Dobson-stone et al, 2020)
Seven rare missense variants in CYLD have been identified in 7 (0.72%) patients among 978 sALS patients, and two (4.3%) rare missense variants were identified among the 46 familial ALS (fALS) cases, where familial cases had a relatively higher variation frequency
Summary
A heterozygous missense variant in CYLD Lysine 63 Deubiquitinase gene (CYLD) was found to co-segregate with the FTD-ALS in an autosomal dominant inherited European Australian family (Dobson-stone et al, 2020). Further functional studies revealed that mutated CYLD can lead to an increased lysine 63 deubiquitinase activity and gave rise to the pathogenesis of ALS and FTD (Dobson-stone et al, 2020). The current study aimed to study the role of CYLD in Chinese patients with ALS. We aimed to (1) systematically screen the mutations of CYLD in a large cohort of Chinese ALS patients, (2) study the genotype–phenotype correlation, and (3) explore the role of CYLD in ALS via rare variants burden analysis
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