A small deletion in C9orf72 hides a proportion of expansion carriers in FTLD

Frontotemporal lobar degeneration is a highly familial disease and the most common known genetic cause is the repeat expansion mutation in the gene C9orf72. We have identified 2 brothers with an expansion mutation in C9orf72 using Southern blotting that is undetectable using repeat-primed polymerase chain reaction. Sequencing using high concentrations of DNA denaturants of a bacterial artificial chromosome clone obtained from one of the brothers identified a 10-base pair deletion adjacent to the expansion that presumably confers strong secondary structure that interferes with the genotyping. Using an alternative method, we have identified missed expansion carriers in our cohort, and this number has increased by approximately 25%. This observation has important implications for patients undergoing genetic testing for C9orf72.

• Publication year

  2015

• Venue

  Neurobiology of Aging

• Publication date

  2015-03-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.neurobiolaging.2014.12.009PMID 25595499PMCID 4353501
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Dipeptide repeat protein toxicity in frontotemporal lobar degeneration and in motor neurone disease associated with expansions in C9ORF72-a cautionary note.

  2015cited by this paper
• A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories

  2014cited by this paper
• Residual association at C9orf72 suggests an alternative amyotrophic lateral sclerosis-causing hexanucleotide repeat

  2013cited by this paper
• Dipeptide repeat proteins are present in the p62 positive inclusions in patients with frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72

  2013cited by this paper
• Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population.

  2013cited by this paper
• Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS.

  2013cited by this paper
• The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS

  2013cited by this paper
• A Pan-European Study of the C9orf72 Repeat Associated with FTLD: Geographic Prevalence, Genomic Instability, and Intermediate Repeats

  2012cited by this paper
• The chromosome 9 ALS and FTD locus is probably derived from a single founder

  2012cited by this paper
• Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study

  2012cited by this paper
• Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.

  2011cited by this paper
• A harmonized classification system for FTLD-TDP pathology

  2011cited by this paper
• A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.

  2011cited by this paper
• Frontotemporal lobar degeneration: clinical and pathological relationships

  2007cited by this paper
• Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17

  2006cited by this paper
• Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17

  1998cited by this paper

• Frequency of C9orf72, GRN, and MAPT pathogenic variants in patients recruited at the Belgrade Memory Center

  2024cites this paper
• C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity

  2023influential citation
• Aspects of degradation and translation of the expanded C9orf72 hexanucleotide repeat RNA

  2023cites this paper
• C9orf72 Repeat Expansion Discordance in 6 Multigenerational Kindreds

  2023cites this paper
• The Psychiatric Misdiagnosis of Behavioral Variant Frontotemporal Dementia in a Colombian Sample

  2021cites this paper
• Sizing, stabilising, and cloning repeat-expansions for gene targeting constructs

  2020cites this paper
• Genetic Testing for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: Impact on Clinical Management.

  2020cites this paper
• Variable reporting of C9orf72 and a high rate of uncertain results in ALS genetic testing

  2019cites this paper
• The C9orf72 hexanucleotide repeat expansion presents a challenge for testing laboratories and genetic counseling

  2019cites this paper
• Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

  2018influential citation
• Comprehensive genotyping of the C9orf72 hexanucleotide repeat region in 2095 ALS samples from the NINDS collection using a two-mode, long-read PCR assay

  2018influential citation
• The Genetics of C9orf72 Expansions.

  2018cites this paper
• Validation of a Long-Read PCR Assay for Sensitive Detection and Sizing of C9orf72 Hexanucleotide Repeat Expansions.

  2018cites this paper
• C9orf72 hexanucleotide repeat expansions and Ataxin 2 intermediate length repeat expansions in Indian patients with amyotrophic lateral sclerosis.

  2017cites this paper
• A PCR-based protocol to accurately size C9orf72 intermediate-length alleles.

  2017cites this paper
• Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study

  2017cites this paper
• Improved PCR based methods for detecting C9orf72 hexanucleotide repeat expansions

  2016cites this paper
• C9orf72 is differentially expressed in the central nervous system and myeloid cells and consistently reduced in C9orf72, MAPT and GRN mutation carriers

  2016cites this paper
• Unstable repeat expansions in neurodegenerative diseases: nucleocytoplasmic transport emerges on the scene.

  2016cites this paper
• Frontotemporal lobar dementia and amyotrophic lateral sclerosis associated with c9orf72 expansion.

  2015cites this paper
• Modelling C9orf72-linked frontotemporal dementia and amyotrophic lateral sclerosis

  2015cites this paper
• Molecular Genetics and Prenatal Diagnosis

  2015cites this paper
• Psychosis associated with expansions in the C9orf72 gene: the influence of a 10 base pair gene deletion

  2015cites this paper