title: Semi-automated quantification of C9orf72 expansion size reveals inverse correlation between hexanucleotide repeat number and disease duration in frontotemporal degeneration.
abstract: We investigated whether chromosome 9 open reading frame 72 hexanucleotide repeat expansion (C9orf72 expansion) size in peripheral DNA was associated with clinical differences in frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) linked to C9orf72 repeat expansion mutations. A novel quantification workflow was developed to measure C9orf72 expansion size by Southern blot densitometry in a cross-sectional cohort of C9orf72 expansion carriers with FTD (n = 39), ALS (n = 33), both (n = 35), or who are unaffected (n = 21). Multivariate linear regressions were performed to assess whether C9orf72 expansion size from peripheral DNA was associated with clinical phenotype, age of disease onset, disease duration and age at death. Mode values of C9orf72 expansion size were significantly shorter in FTD compared to ALS (p = 0.0001) but were not associated with age at onset in either FTD or ALS. A multivariate regression model correcting for patient's age at DNA collection and disease phenotype revealed that C9orf72 expansion size is significantly associated with shorter disease duration (p = 0.0107) for individuals with FTD, but not with ALS. Despite considerable somatic instability of the C9orf72 expansion, semi-automated expansion size measurements demonstrated an inverse relationship between C9orf72 expansion size and disease duration in patients with FTD. Our finding suggests that C9orf72 repeat size may be a molecular disease modifier in FTD linked to hexanucleotide repeat expansion.
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA, 19104-4283, USA, suher@mail.med.upenn.edu.
authors.forename: EunRan
authors.initials: E
authors.lastname: Suh
authors.forename: Edward B
authors.initials: EB
authors.lastname: Lee
authors.forename: Donald
authors.initials: D
authors.lastname: Neal
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Wood
authors.forename: Jon B
authors.initials: JB
authors.lastname: Toledo
authors.forename: Lior
authors.initials: L
authors.lastname: Rennert
authors.forename: David J
authors.initials: DJ
authors.lastname: Irwin
authors.forename: Corey T
authors.initials: CT
authors.lastname: McMillan
authors.forename: Bryan
authors.initials: B
authors.lastname: Krock
authors.forename: Lauren B
authors.initials: LB
authors.lastname: Elman
authors.forename: Leo F
authors.initials: LF
authors.lastname: McCluskey
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
authors.forename: Sharon X
authors.initials: SX
authors.lastname: Xie
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
mesh_terms: D017668:Age of Onset; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood / Q000235:genetics* / Q000503:physiopathology*; D015139:Blotting, Southern; D000073885:C9orf72 Protein; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D042622:DNA Repeat Expansion; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000097:blood / Q000235:genetics* / Q000503:physiopathology*; D060005:Genotyping Techniques; D006239:Haplotypes; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010363:Pattern Recognition, Automated; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins