title: C9ORF72 expansion in a family with bipolar disorder.
abstract: OBJECTIVE
  To investigate the role in bipolar disorder of the C9ORF72 hexanucleotide repeat expansion responsible for frontotemporal lobe dementia and amyotrophic lateral sclerosis.
  
  
  METHODS
  Eighty-nine subjects from a previously described panel of individuals with bipolar disorder ascertained for genetic studies were screened to detect expansion of the C9ORF72 repeat. One two-generation family with bipolar disorder and an expanded repeat was characterized in depth using molecular diagnostics, imaging, histopathology, and neurological and neuropsychological evaluation.
  
  
  RESULTS
  One proband, with the typical clinical presentation of bipolar disorder, carried an expanded C9ORF72 allele of heterogeneous length between 14 and 20 kilobases (kb) as assessed by Southern blot. The expanded allele was inherited from a parent with atypical, late onset clinical features of bipolar disorder, who subsequently progressed to frontotemporal lobe dementia. The expansion in peripheral blood of the parent ranged from 8.5 to 20 kb. Cultured lymphoblastoid cells from this parent exhibited a homogeneous expansion of only 8.5 kb.
  
  
  CONCLUSIONS
  The disease course in the two generations described here demonstrates that expansion of the C9ORF72 may be associated with a form of bipolar disorder that presents clinically with classic phenomenology and progression to neurodegenerative disease. The frequency in our bipolar disorder cohort was only 1%, indicating that C9ORF72 is not a major contributor to bipolar disorder. DNA from cultured cells may be biased towards shorter repeats and nonrepresentative of the endogenous C9ORF72 expansion.
authors.affiliation: Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor, MI 48109-5618, USA. meislerm@umich.edu
authors.forename: Miriam H
authors.initials: MH
authors.lastname: Meisler
authors.forename: Adrienne E
authors.initials: AE
authors.lastname: Grant
authors.forename: Julie M
authors.initials: JM
authors.lastname: Jones
authors.forename: Guy M
authors.initials: GM
authors.lastname: Lenk
authors.forename: Fang
authors.initials: F
authors.lastname: He
authors.forename: Peter K
authors.initials: PK
authors.lastname: Todd
authors.forename: Masoud
authors.initials: M
authors.lastname: Kamali
authors.forename: Roger L
authors.initials: RL
authors.lastname: Albin
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
authors.forename: Scott A
authors.initials: SA
authors.lastname: Langenecker
authors.forename: Melvin G
authors.initials: MG
authors.lastname: McInnis
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000150:complications / Q000235:genetics* / Q000473:pathology; D000073885:C9orf72 Protein; D002478:Cells, Cultured; D015331:Cohort Studies; D042622:DNA Repeat Expansion / Q000235:genetics*; D018450:Disease Progression; D005192:Family Health; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008214:Lymphocytes / Q000502:physiology; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000235:genetics; D009483:Neuropsychological Tests; D011506:Proteins / Q000235:genetics*; D011569:Psychiatric Status Rating Scales
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins
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