Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/79352
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Type: Journal article
Title: Frontotemporal dementia-amyotrophic lateral sclerosis syndrome locus on chromosome 16p12.1-q12.2: genetic, clinical and neuropathological analysis
Author: Dobson-Stone, C.
Luty, A.
Thompson, E.
Blumbergs, P.
Brooks, W.
Short, C.
Field, C.
Panegyres, P.
Hecker, J.
Solski, J.
Blair, I.
Fullerton, J.
Halliday, G.
Schofield, P.
Kwok, J.
Citation: Acta Neuropathologica, 2013; 125(4):523-533
Publisher: Springer
Issue Date: 2013
ISSN: 0001-6322
1432-0533
Statement of
Responsibility: 
Carol Dobson-Stone, Agnes A. Luty, Elizabeth M. Thompson, Peter Blumbergs, William S. Brooks, Cathy L. Short, Colin D. Field, Peter K. Panegyres, Jane Hecker, Jennifer A. Solski, Ian P. Blair, Janice M. Fullerton, Glenda M. Halliday, Peter R. Schofield, John B. J. Kwok
Abstract: Numerous families exhibiting both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have been described, and although many of these have been shown to harbour a repeat expansion in C9ORF72, several C9ORF72-negative FTD-ALS families remain. We performed neuropathological and genetic analysis of a large European Australian kindred (Aus-12) with autosomal dominant inheritance of dementia and/or ALS. Affected Aus-12 members developed either ALS or dementia; some of those with dementia also had ALS and/or extrapyramidal features. Neuropathology was most consistent with frontotemporal lobar degeneration with type B TDP pathology, but with additional phosphorylated tau pathology consistent with corticobasal degeneration. Aus-12 DNA samples were negative for mutations in all known dementia and ALS genes, including C9ORF72 and FUS. Genome-wide linkage analysis provided highly suggestive evidence (maximum multipoint LOD score of 2.9) of a locus on chromosome 16p12.1–16q12.2. Affected individuals shared a chromosome 16 haplotype flanked by D16S3103 and D16S489, spanning 37.9 Mb, with a smaller suggestive disease haplotype spanning 24.4 Mb defined by recombination in an elderly unaffected individual. Importantly, this smaller region does not overlap with FUS. Whole-exome sequencing identified four variants present in the maximal critical region that segregate with disease. Linkage analysis incorporating these variants generated a maximum multipoint LOD score of 3.0. These results support the identification of a locus on chromosome 16p12.1–16q12.2 responsible for an unusual cluster of neurodegenerative phenotypes. This region overlaps with a separate locus on 16q12.1–q12.2 reported in an independent ALS family, indicating that this region may harbour a second major locus for FTD-ALS.
Keywords: Frontotemporal dementia; Amyotrophic lateral sclerosis; Motor neuron disease; Corticobasal degeneration; Tau; TDP-43
Rights: © The Author(s) 2013. This article is published with open access at Springerlink.com
RMID: 0020124836
DOI: 10.1007/s00401-013-1078-9
Grant ID: http://purl.org/au-research/grants/nhmrc/157209
http://purl.org/au-research/grants/nhmrc/630434
http://purl.org/au-research/grants/nhmrc/276401
http://purl.org/au-research/grants/nhmrc/510217
http://purl.org/au-research/grants/nhmrc/630428
Appears in Collections:Paediatrics publications

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