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

• 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
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2014.12.009

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.