Abstract
Familial adult myoclonus epilepsy (FAME) is a rare autosomal dominant disorder characterized by adult onset, involuntary muscle jerks, cortical myoclonus and occasional seizures. FAME is genetically heterogeneous with more than 70 families reported worldwide and five potential disease loci. The efforts to identify potential causal variants have been unsuccessful in all but three families. To date, linkage analysis has been the main approach to find and narrow FAME critical regions. We propose an alternative method, pedigree free identity-by-descent (IBD) mapping, that infers regions of the genome between individuals that have been inherited from a common ancestor. IBD mapping provides an alternative to linkage analysis in the presence of allelic and locus heterogeneity by detecting clusters of individuals who share a common allele. Succeeding IBD mapping, gene prioritization based on gene co-expression analysis can be used to identify the most promising candidate genes. We performed an IBD analysis using high-density single nucleotide polymorphism (SNP) array data followed by gene prioritization on a FAME cohort of ten European families and one Australian/New Zealander family; eight of which had known disease loci. By identifying IBD regions common to multiple families, we were able to narrow the FAME2 locus to a 9.78 megabase interval within 2p11.2–q11.2. We provide additional evidence of a founder effect in four Italian families and allelic heterogeneity with at least four distinct founders responsible for FAME at the FAME2 locus. In addition, we suggest candidate disease genes using gene prioritization based on gene co-expression analysis.
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Acknowledgments
We thank the families for their participation in this study. This work was supported by the National Health and Medical Research Council (NHMRC) Program Grant (628952) to J.G. M.B. was supported by an NHMRC Senior Research Fellowship (1002098) and NHMRC Program Grant (APP1054618). L.H. was supported by The John and Patricia Farrant Scholarship and the Australian Postgraduate Award Scholarship. This work was also supported by Victorian State Government Operational Infrastructure Support, Australian Government NHMRC IRIISS funding, Fondation Maladies rares, Assistance publique des hôpitaux de Paris (AP-HP) and Université Pierre et Marie-Curie (UPMC).
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
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Henden, L., Freytag, S., Afawi, Z. et al. Identity by descent fine mapping of familial adult myoclonus epilepsy (FAME) to 2p11.2–2q11.2. Hum Genet 135, 1117–1125 (2016). https://doi.org/10.1007/s00439-016-1700-8
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DOI: https://doi.org/10.1007/s00439-016-1700-8