scholarly journals The Frequency of Genetic Mutations Associated With Behavioral Variant Frontotemporal Dementia in Chinese Han Patients

2021 ◽  
Vol 13 ◽  
Author(s):  
Li Liu ◽  
Bo Cui ◽  
Min Chu ◽  
Yue Cui ◽  
Donglai Jing ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Genetic Variants ◽  
Genetic Mutations ◽  
Chinese Han ◽  
Behavioral Variant Frontotemporal Dementia ◽  
Pathogenic Variants ◽  
Hexanucleotide Repeat ◽  
Mapt Gene ◽  
Repeat Expansions ◽  
Expansion Mutation

BackgroundBehavioral variant frontotemporal dementia (bvFTD) is a clinically heterogeneous syndrome with high heredity. However, the frequencies of mutations associated with bvFTD have yet to be determined. The aim of the current study was to investigate the frequency of Chinese Han patients harboring genetic bvFTD variants.MethodsA total of 49 bvFTD patients selected from our frontotemporal lobar degeneration database, including 14 familial cases belonging to eight families and 35 sporadic cases were consecutively recruited from July 2014 to December 2019 at Xuanwu Hospital (Beijing, China). Whole-exome sequencing (WES) was performed and repeat-primed PCR was used to test samples for the C9orf72 hexanucleotide repeat expansion mutation. The frequency of genetic variants and the pathogenicity of the novel variants were analyzed.ResultsTen pathogenic or likely pathogenic variants were identified in 17 bvFTD patients, including C9orf72 repeat expansions, six previously reported mutations and three novel mutations (MAPT p. R5C, p. D54N, GRN p. P451L). Genetic mutations accounted for 27.9% (12/43) of total cases, 87.5% (7/8) of patients with familial bvFTD, and 14.3% (5/35) with sporadic bvFTD. Pathogenic variants mostly occurred in MAPT gene (20.9%, 9/43), followed by C9orf72 repeat expansions (2.3%, 1/43), GRN gene (2.3%, 1/43) and FUS gene (2.3%, 1/43).ConclusionThere was a high prevalence of genetic variants in Chinese bvFTD patients, highlighting the necessity of genetic testing for bvFTD.

scholarly journals Genome-wide association study of frontotemporal dementia identifies a C9ORF72 haplotype with a median of 12-G4C2 repeats that predisposes to pathological repeat expansions

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lianne M. Reus ◽  
Iris E. Jansen ◽  
Merel O. Mol ◽  
Fred van Ruissen ◽  
Jeroen van Rooij ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Genetic Variants ◽  
Genome Wide Association ◽  
Risk Haplotype ◽  
Genome Wide Association Studies ◽  
Founder Haplotype ◽  
Risk Variants ◽  
Genome Wide ◽  
Rare Genetic Variants ◽  
Repeat Expansions

AbstractGenetic factors play a major role in frontotemporal dementia (FTD). The majority of FTD cannot be genetically explained yet and it is likely that there are still FTD risk loci to be discovered. Common variants have been identified with genome-wide association studies (GWAS), but these studies have not systematically searched for rare variants. To identify rare and new common variant FTD risk loci and provide more insight into the heritability of C9ORF72-related FTD, we performed a GWAS consisting of 354 FTD patients (including and excluding N = 28 pathological repeat carriers) and 4209 control subjects. The Haplotype Reference Consortium was used as reference panel, allowing for the imputation of rare genetic variants. Two rare genetic variants nearby C9ORF72 were strongly associated with FTD in the discovery (rs147211831: OR = 4.8, P = 9.2 × 10−9, rs117204439: OR = 4.9, P = 6.0 × 10−9) and replication analysis (P < 1.1 × 10−3). These variants also significantly associated with amyotrophic lateral sclerosis in a publicly available dataset. Using haplotype analyses in 1200 individuals, we showed that these variants tag a sub-haplotype of the founder haplotype of the repeat expansion that was previously found to be present in virtually all pathological C9ORF72 G4C2 repeat lengths. This new risk haplotype was 10 times more likely to contain a C9ORF72 pathological repeat length compared to founder haplotypes without one of the two risk variants (~22% versus ~2%; P = 7.70 × 10−58). In haplotypes without a pathologic expansion, the founder risk haplotype had a higher number of repeats (median = 12 repeats) compared to the founder haplotype without the risk variants (median = 8 repeats) (P = 2.05 × 10−260). In conclusion, the identified risk haplotype, which is carried by ~4% of all individuals, is a major risk factor for pathological repeat lengths of C9ORF72 G4C2. These findings strongly indicate that longer C9ORF72 repeats are unstable and more likely to convert to germline pathological C9ORF72 repeat expansions.

scholarly journals Analysis of Heritability Across the Clinical Phenotypes of Frontotemporal Dementia and the Frequency of the C9ORF72 in a Colombian Population

2021 ◽  
Vol 12 ◽  
Author(s):  
Andrea López-Cáceres ◽  
María Velasco-Rueda ◽  
Elkin Garcia-Cifuentes ◽  
Ignacio Zarante ◽  
Diana Matallana
Keyword(s):  
Frontotemporal Dementia ◽  
Single Gene ◽  
Initial Report ◽  
C9orf72 Expansion ◽  
Clinical Phenotypes ◽  
Hereditary Risk ◽  
Familial Cases ◽  
Risk Criteria ◽  
Hexanucleotide Repeat ◽  
Repeat Expansions

Frontotemporal dementia (FTD) is a highly heritable condition. Up to 40% of FTD is familial and an estimated 15% to 40% is due to single-gene mutations. It has been estimated that the G4C2 hexanucleotide repeat expansions in the C9ORF72 gene can explain up to 37.5% of the familial cases of FTD, especially in populations of Caucasian origin. The purpose of this paper is to evaluate hereditary risk across the clinical phenotypes of FTD and the frequency of the G4C2 expansion in a Colombian cohort diagnosed with FTD.Methods: A total of 132 FTD patients were diagnosed according to established criteria in the behavioral variant FTD, logopenic variant PPA, non-fluent agrammatic PPA, and semantic variant PPA. Hereditary risk across the clinical phenotypes was established in four categories that indicate the pathogenic relationship of the mutation: high, medium, low, and apparently sporadic, based on those proposed by Wood and collaborators. All subjects were also examined for C9ORF72 hexanucleotide expansion (defined as &gt;30 repetitions).Results: There were no significant differences in the demographic characteristics of the patients between the clinical phenotypes of FTD. The higher rate phenotype was bvFTD (62.12%). In accordance with the risk classification, we found that 72 (54.4%) complied with the criteria for the sporadic cases; for the familial cases, 23 (17.4%) fulfilled the high-risk criteria, 23 (17.4%) fulfilled the low risk criteria, and 14 (10.6%) fulfilled the criteria to be classified as subject to medium risk. C9ORF72 expansion frequency was 0.76% (1/132).Conclusion: The FTD heritability presented in this research was very similar to the results reported in the literature. The C9ORF72 expansion frequency was low. Colombia is a triethnic country, with a high frequency of genetic Amerindian markers; this shows consistency with the present results of a low repetition frequency. This study provides an initial report of the frequency for the hexanucleotide repeat expansions in C9ORF72 in patients with FTD in a Colombian population and paves the way for further study of the possible genetic causes of FTD in Colombia.

scholarly journals C9orf72 Repeat Expansions in Rapid Eye Movement Sleep Behaviour Disorder

2014 ◽  
Vol 41 (6) ◽  
pp. 759-762 ◽  
Author(s):  
Hussein Daoud ◽  
Ronald B. Postuma ◽  
Cynthia V. Bourassa ◽  
Daniel Rochefort ◽  
Maude Turcotte Gauthier ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Eye Movement ◽  
Repeat Expansion ◽  
Risk Haplotype ◽  
Rapid Eye Movement ◽  
Rapid Eye Movement Sleep ◽  
Hexanucleotide Repeat ◽  
Repeat Expansions ◽  
Lateral Sclerosis

AbstractBackground: A large hexanucleotide repeat expansion in C9orf72 has been identified as the most common genetic cause in familial amyotrophic lateral sclerosis and frontotemporal dementia. Rapid Eye Movement Sleep Behavior Disorder (RBD) is a sleep disorder that has been strongly linked to synuclein-mediated neurodegeneration. The aim of this study was to evaluate the role of the C9orf72 expansions in the pathogenesis of RBD. Methods: We amplified the C9orf72 repeat expansion in 344 patients with RBD by a repeat-primed polymerase chain reaction assay. Results: We identified two RBD patients carrying the C9orf72 repeat expansion. Most interestingly, these patients have the same C9orf72 associated-risk haplotype identified in 9p21-linked amyotrophic lateral sclerosis and frontotemporal dementia families. Conclusions: Our study enlarges the phenotypic spectrum associated with the C9orf72 hexanucleotide repeat expansions and suggests that, although rare, this expansion may play a role in the pathogenesis of RBD.

Frequency of common genetic forms of frontotemporal dementia in a Russian cohort of patients

2020 ◽  
pp. 30-32
Author(s):  
Ю.А. Шпилюкова ◽  
Е.Ю. Федотова ◽  
Н.Ю. Абрамычева ◽  
С.Н. Иллариошкин
Keyword(s):  
Frontotemporal Dementia ◽  
Clinical Phenotypes ◽  
Mapt Gene ◽  
First Time

Впервые в российской популяции на когорте пациентов с клиническим диагнозом ЛВД исследована частота встречаемости мутаций в наиболее частых генах, ассоциированных с данным заболеванием. Наибольшая часто мутирующими являются гены C9orf72 и GRN. Реже всего встречаются мутации в гене MAPT, что возможно связано с неравномерным представительством клинических фенотипов в нашей выборке. For the first time in the Russian cohort of FTD patients the frequency of mutations in the most common genes associated with this disease was studied. The most frequently mutating are the genes C9orf72 and GRN. Mutations in the MAPT gene are least likely to occur, which is probably due to the uneven representation of clinical phenotypes in our sample.

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