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

Abstract 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...

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Bibliographic Details
Published in:Neurobiology of aging 2015-03, Vol.36 (3), p.1601.e1-1601.e5
Main Authors: Rollinson, Sara, Bennion Callister, Janis, Young, Kate, Ryan, Sarah J, Druyeh, Ronald, Rohrer, Jonathan D, Snowden, Julie, Richardson, Anna, Jones, Matt, Harris, Jenny, Davidson, Yvonne, Robinson, Andrew, Ealing, John, Johnson, Janel O, Traynor, Bryan, Mead, Simon, Mann, David, Pickering-Brown, Stuart M
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
ALS
C9orf72
C9orf72 Protein
Cohort Studies
DNA Repeat Expansion - genetics
Female
Frontotemporal lobar degeneration
Frontotemporal Lobar Degeneration - epidemiology
Frontotemporal Lobar Degeneration - genetics
FTLD
Gene Deletion
Genetic Report Abstract
Genetic Testing - methods
Heterozygote
Humans
Internal Medicine
Male
Middle Aged
Mutation - genetics
Neurology
Polymerase Chain Reaction - methods
Proteins - genetics
Repeat expansion
Sequence Analysis, DNA - methods
Young Adult
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Summary:Abstract 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.
ISSN:0197-4580
1558-1497
DOI:10.1016/j.neurobiolaging.2014.12.009