C9orf72 hexanucleotide repeat length in older population: normal variation and effects on cognition

Kaivola, Karri; Kiviharju, Anna; Jansson, Lilja; Rantalainen, Ville; Eriksson, Johan G.; Strandberg, Timo; Laaksovirta, Hannu; Renton, Alan E.; Traynor, Bryan J.; Myllykangas, Liisa; Tienari, Pentti J.

doi:10.1016/j.neurobiolaging.2019.02.026

Cited by 16 publications

(27 citation statements)

References 39 publications

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“…Our control group consisted of individuals from six cohorts. We have previously determined the C9orf72 hexanucleotide repeat lengths in four cohorts and the cohort descriptions have been previously published [ 13 ]. In brief, the Vantaa 85+ study consists of 553 individuals of at least 85 years of age, who were living in the city of Vantaa, Finland on April 1st 1991 (DNA available in 486).…”

Section: Methodsmentioning

confidence: 99%

“…We extracted DNA using standard methods from peripheral blood leukocytes (5 cohorts) or saliva (PLASTICITY cohort). We assessed the C9orf72 hexanucleotide repeat alleles as previously described [ 21 ] with minor modifications [ 13 ]. In brief, for all samples, we first assessed repeat lengths using repeat-primed PCR (RP-PCR) followed by capillary electrophoresis and the results were visualized using the GeneMapper software v6 (ThermoFisher).…”

Section: Methodsmentioning

confidence: 99%

“…Samples that showed the typical saw tooth pattern in RP-PCR and did not produce longer amplicon in over-the-repeat PCR were categorized as expansions. The longest non-expanded (amplifiable) discrete allele we could detect was 45 repeats, and we used it as the expansion threshold [ 13 ]. Examples of RP-PCR capillary electrophoresis chromatograms and over-the-repeat PCR analyses are in Additional file 1 : Supplementary Figure 1.…”

Section: Methodsmentioning

confidence: 99%

“…The minimum pathogenic repeat length is unknown, but the threshold of 30 repeats has been commonly used. This threshold might be underestimated since we recently found that about 0.4% of aged Finns carried 30–45 repeat alleles and these individuals had no apparent increase in the frequency of neurodegenerative or psychiatric diseases [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population

Kaivola

Salmi

Jansson

et al. 2020

acta neuropathol commun

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The hexanucleotide repeat expansion in intron 1 of the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In addition to the effects of the pathogenic expansion, a role of intermediate-length alleles has been suggested in ALS, corticobasal degeneration and Parkinson’s disease. Due to the rarity of intermediate-length alleles with over 20 repeats and the geographical variability in their frequency, large studies that account for population stratification are needed to elucidate their effects. To this aim, we used repeat-primed PCR and confirmatory PCR assays to determine the C9orf72 repeat allele lengths in 705 ALS patients and 3958 controls from Finland. After exclusion of expansion carriers (25.5% of the ALS patients and 0.2% of the controls), we compared the frequency of intermediate-length allele carriers of 525 ALS cases and 3950 controls using several intermediate-length allele thresholds (7–45, 17–45, 21–45, 24–45 and 24–30). The carriership of an intermediate-length allele did not associate with ALS (Fisher’s test, all p ≥ 0.15) nor was there any association with survival (p ≥ 0.33), when we divided our control group into three age groups (18–65, 66–84 and 85–105 years). Carriership of two intermediate-length alleles was associated with ALS, when the longer allele was ≥ 17 repeats (p = 0.002, OR 5.32 95% CI 2.02–14.05) or ≥ 21 repeats (p = 0.00016, OR 15.21 95% CI 3.79–61.0). Our results show that intermediate-length alleles are a risk factor of ALS when present in both alleles, whereas carrying just one intermediate-length allele was not associated with ALS or survival.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population

Kaivola

Salmi

Jansson

et al. 2020

acta neuropathol commun

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“…Note on the assumption that C9orf72 expansions will be absent from controls: two studies have assessed the frequency of C9orf72 expansions in healthy controls, both arriving at a frequency of approximately 0.2% of individuals (Beck et al 2013; Kaivola et al 2019) (this would be equivalent to approximately 1 carrier in our control set of 542 individuals). However, in one of these studies, they also assessed for other neurologic diseases, and found that 4 of 6 individuals with C9orf72 expansions (out of 3142) had another neurologic disease (Kaivola et al 2019), leaving only 2 expansion carriers out of 3142 individuals in that study. Therefore, the assumption that no repeat expansion carriers are present in the control set we selected where individuals with a family history of any neurologic disease have been excluded is not unreasonable.…”

Section: Supplemental Materialsmentioning

confidence: 99%

Genome sequencing for early-onset dementia: high diagnostic yield and frequent observation of multiple contributory alleles

Cochran

McKinley

Cochran

et al. 2019

Preprint

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21We assessed the utility of genome sequencing for early-onset dementia. Participants were selected 22 from a memory disorders clinic. Genome sequencing was performed along with C9orf72 repeat 23 expansion testing. All returned sequencing results were Sanger validated clinically. Prior clinical 24 diagnoses included Alzheimer's disease, frontotemporal dementia, and unspecified dementia. The 25 mean age-of-onset was 54 (41-76). 50% of patients had a strong family history, 37.5% had some, and 26 12.5% had no known family history. Nine of 32 patients (28%) had a variant defined as pathogenic or 27 likely pathogenic (P/LP) by American College of Medical Genetics standards, including variants in APP, 28 C9orf72, CSF1R, and MAPT. Nine patients (including three with P/LP variants) harbored established 29 risk alleles with moderate penetrance (odds ratios of about 2-5) in ABCA7, AKAP9, GBA, PLD3,

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Evidence‐based consensus guidelines for ALS genetic testing and counseling

Roggenbuck,

Eubank,

Wright

et al. 2023

Ann Clin Transl Neurol

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ObjectiveAdvances in amyotrophic lateral sclerosis (ALS) gene discovery, ongoing gene therapy trials, and patient demand have driven increased use of ALS genetic testing. Despite this progress, the offer of genetic testing to persons with ALS is not yet “standard of care.” Our primary goal is to develop clinical ALS genetic counseling and testing guidelines to improve and standardize genetic counseling and testing practice among neurologists, genetic counselors or any provider caring for persons with ALS.MethodsCore clinical questions were identified and a rapid review performed according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA‐P) 2015 method. Guideline recommendations were drafted and the strength of evidence for each recommendation was assessed by combining two systems: the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) System and the Evaluation of Genomic Applications in Practice and Prevention (EGAPP). A modified Delphi approach was used to reach consensus among a group of content experts for each guideline statement.ResultsA total of 35 guideline statements were developed. In summary, all persons with ALS should be offered single‐step genetic testing, consisting of a C9orf72 assay, along with sequencing of SOD1, FUS, and TARDBP, at a minimum. The key education and genetic risk assessments that should be provided before and after testing are delineated. Specific guidance regarding testing methods and reporting for C9orf72 and other genes is provided for commercial laboratories.InterpretationThese evidence‐based, consensus guidelines will support all stakeholders in the ALS community in navigating benefits and challenges of genetic testing.

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C9orf72 hexanucleotide repeat length in older population: normal variation and effects on cognition

Cited by 16 publications

References 39 publications

Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population

Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population

Genome sequencing for early-onset dementia: high diagnostic yield and frequent observation of multiple contributory alleles

Evidence‐based consensus guidelines for ALS genetic testing and counseling

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