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C9 ORF 72 expansion in a family with bipolar disorder
Author(s) -
Meisler Miriam H,
Grant Adrienne E,
Jones Julie M,
Lenk Guy M,
He Fang,
Todd Peter K,
Kamali Masoud,
Albin Roger L,
Lieberman Andrew P,
Langenecker Scott A,
McInnis Melvin G
Publication year - 2013
Publication title -
bipolar disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.285
H-Index - 129
eISSN - 1399-5618
pISSN - 1398-5647
DOI - 10.1111/bdi.12063
Subject(s) - c9orf72 , bipolar disorder , trinucleotide repeat expansion , frontotemporal dementia , proband , dementia , amyotrophic lateral sclerosis , psychology , medicine , allele , genetics , psychiatry , disease , biology , mutation , cognition , gene
Objective To investigate the role in bipolar disorder of the C9 ORF 72 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 C9 ORF 72 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 C9 ORF 72 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 C9 ORF 72 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 C9 ORF 72 is not a major contributor to bipolar disorder. DNA from cultured cells may be biased towards shorter repeats and nonrepresentative of the endogenous C9 ORF 72 expansion.