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

• DOI: 10.1007/s00439-016-1700-8
• Publication Date: 2016-07-01T08:34:48Z
• Authors: Lyndal Henden; Saskia Freytag; Zaid Afawi; Sara Baldassari; Samuel F. Berkovic; Francesca Bisulli; Laura Canafoglia; Giorgio Casari; Douglas Ewan Crom...; Christel Depienne; Jozef Gecz; Renzo Guerrini; Ingo Helbig; Edouard Hirsch; Boris Keren; Karl Martin Klein; Pierre Labauge; Eric LeGuern; Laura Licchetta; Davide Mei; Caroline Nava; Tommaso Pippucci; Gabrielle Rudolf; Ingrid Eileen Sch...; Pasquale Striano; Paolo Tinuper; Federico Zara; Mark Corbett; Melanie Bahlo
• Keywords: Male; 0301 basic medicine; 572; Genetics; Genetics (clinical); Genotype; Medicine (all); Genetics; Genetics (clinical); Genetic Linkage; Epilepsies, Myoclonic; Epilepsies; [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics; Polymorphism, Single Nucleotide; Chromosomes; Genetic Heterogeneity; 03 medical and health sciences; Seizures; Humans; Polymorphism; Alleles; Chromosome Mapping; Muscle, Smooth; Single Nucleotide; Founder Effect; Pedigree; 3. Good health; [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics; Chromosomes, Human, Pair 2; Pair 2; Muscle; epilepsy; Female; Smooth; Myoclonic; Human

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.