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We previously reported1 that expansions in the C9orf72 gene, identified by Southern blotting or using a repeat primed PCR assay,2 may go undetected using an alternative, standard PCR assay.3 We attributed this discrepancy to a 10 base pair deletion adjacent to the expansion which was presumed to interfere with genotyping.1 To determine the possible clinical and pathological relevance of the deletion, we compared patients in whom the C9orf72 expansion was detected using the Renton3 assay (C9 reference group) with those carrying an expansion not detected by this method (deletion group).
The criteria for inclusion in the study were: (A) patients had been investigated and diagnosed with dementia within a single, specialist dementia clinic, (B) they had donated DNA as part of an ethically approved study into the molecular genetics of dementia and (C) expansions in the C9orf72 gene were identified using one or more standard procedures.1–3 An additional patient, in whom pathological examination showed p62 positive neuronal inclusions immunoreactive for the dipeptide repeat proteins, poly-GA, poly-GP and poly-GR, was also included since such histological findings are considered pathognomonic of the presence of an expansion in C9orf72.4 …
Contributors JSS was involved in conception and design, data acquisition, analysis and interpretation, drafting and revision of the manuscript. JH, JA, JCT, AMR, MSJ and DN were involved in acquisition of clinical data, critical review and approval of the manuscript. YSD and ACR were involved in pathological analysis of brain tissues and approval of the manuscript. SR and SP-B were involved in acquisition and interpretation of genetic data, critical review and approval of the manuscript. DMM was involved in conception and design, analysis and interpretation of pathological data, drafting and revision of the manuscript.
Funding SP-B receives funding from the Medical Research Council (The Molecular Genetics of Dementia and other Neurodegenerative Disorders MRC G0701441). The Manchester brain donation scheme and work of the Manchester Brain Bank is supported by Alzheimer's Research UK and the Alzheimer's Society through the Brains for Dementia Research Initiative.
Competing interests SP-B is named as co-inventor of a patent covering C9orf72.
Ethics approval Ethical approval was obtained from the Greater Manchester North Research Ethics Committee: ‘The Molecular Genetics of Dementia and other Neurodegenerative Disorders’ Rec ref. 05/Q1405/24; and Newcastle and Tyneside Ethics committee ‘Clinical data in research into degenerative brain disease’ Rec ref. 09/H0906/53+5, ‘Manchester Brain Bank’ Rec ref. 09/H0906/52+5.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Requests for data sharing should be made in writing to the corresponding author. Requests will be considered individually at departmental research/clinical governance meetings.