Journal Article

Identity by descent fine mapping of familial adult myoclonus epilepsy (FAME) to 2p11.2–2q11.2

Labauge, Pierre, Helbig, Ingo, Rudolf, Gabrielle, Mei, Davide, LeGuern, Eric, Nava, Caroline, Canafoglia, Laura, Corbett, Mark, Henden, Lyndal, Bisulli, Francesca, Freytag, Saskia, Striano, Pasquale, Keren, Boris, Tinuper, Paolo, Pippucci, Tommaso, Depienne, Christel, Casari, Giorgio, Scheffer, Ingrid Eileen, Gecz, Jozef, Berkovic, Samuel F., Bahlo, Melanie, Guerrini, Renzo, Klein, Karl Martin, Zara, Federico, Crompton, Douglas Ewan, Baldassari, Sara, Afawi, Zaid, Hirsch, Edouard, Licchetta, Laura

2016

Overview

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.

• Publisher: Springer Berlin Heidelberg,Springer,Springer Nature B.V,Springer Verlag
• Subject: Alleles / Analysis / Biomedical and Life Sciences / Biomedicine / Chromosome Mapping / Chromosomes / Chromosomes, Human, Pair 2 / Convulsions & seizures / Epilepsies, Myoclonic - genetics / Epilepsies, Myoclonic - physiopathology / Epilepsy / Family / Female / Founder Effect / Gene Function / Genes / Genetic aspects / Genetic Heterogeneity / Genetic Linkage / Genetics / Genomes / Genomics / Genotype / Human Genetics / Humans / Life Sciences / Male / Medical schools / Metabolic Diseases / Molecular Medicine / Muscle, Smooth - physiopathology / Myoclonus / Neurosciences / Original Investigation / Pedigree / Polymorphism, Single Nucleotide / Seizures - genetics / Seizures - physiopathology / Single nucleotide polymorphisms