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. 2015 Mar;36(3):1601.e1-5.
doi: 10.1016/j.neurobiolaging.2014.12.009. Epub 2014 Dec 12.

Small deletion in C9orf72 hides a proportion of expansion carriers in FTLD

Sara Rollinson  1 , Janis Bennion Callister  1 , Kate Young  1 , Sarah J Ryan  1 , Ronald Druyeh  2 , Jonathan D Rohrer  2 , Julie Snowden  3 , Anna Richardson  3 , Matt Jones  3 , Jenny Harris  3 , Yvonne Davidson  3 , Andrew Robinson  3 , John Ealing  4 , Janel O Johnson  5 , Bryan Traynor  5 , Simon Mead  6 , David Mann  3 , Stuart M Pickering-Brown  7
Affiliations

Small deletion in C9orf72 hides a proportion of expansion carriers in FTLD

Sara Rollinson et al. Neurobiol Aging. 2015 Mar.

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.

Keywords: ALS; C9orf72; FTLD; Frontotemporal lobar degeneration; Repeat expansion.

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Figures

Fig. 1
Fig. 1
Southern blot (as of Mann et al. (2013) for Set A and Beck et al. (2013) for Set B) of C9orf72 of both brothers confirming a repeat expansion is present in both. Set A left to right, marker; negative control, positive control, patient samples. Set (B) left to right; marker; patient samples; positive control; negative control.
Fig. 2
Fig. 2
Ten bp deletion adjacent to the GGGGCC repeat region.
Fig. 3
Fig. 3
Top–repeat primed PCR showing 6 repeats in C9orf72 using the assay by Renton et al. (2011) in a case with the 10 bp deletion. Bottom–the same case genotyped with the assay by DeJesus-Hernandez et al. (2011) showing the expansion also shown by Southern blot. Abbreviation: PCR, polymerase chain reaction.
See this image and copyright information in PMC

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