TY - JOUR
T1 - Identity by descent fine mapping of familial adult myoclonus epilepsy (FAME) to 2p11.2–2q11.2
AU - Henden, Lyndal
AU - Freytag, Saskia
AU - Afawi, Zaid
AU - Baldassari, Sara
AU - Berkovic, Samuel F.
AU - Bisulli, Francesca
AU - Canafoglia, Laura
AU - Casari, Giorgio
AU - Crompton, Douglas Ewan
AU - Depienne, Christel
AU - Gecz, Jozef
AU - Guerrini, Renzo
AU - Helbig, Ingo
AU - Hirsch, Edouard
AU - Keren, Boris
AU - Klein, Karl Martin
AU - Labauge, Pierre
AU - LeGuern, Eric
AU - Licchetta, Laura
AU - Mei, Davide
AU - Nava, Caroline
AU - Pippucci, Tommaso
AU - Rudolf, Gabrielle
AU - Scheffer, Ingrid Eileen
AU - Striano, Pasquale
AU - Tinuper, Paolo
AU - Zara, Federico
AU - Corbett, Mark
AU - Bahlo, Melanie
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84976488253&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/nhmrc/628952
UR - http://purl.org/au-research/grants/nhmrc/1002098
UR - http://purl.org/au-research/grants/nhmrc/1054618
U2 - 10.1007/s00439-016-1700-8
DO - 10.1007/s00439-016-1700-8
M3 - Article
C2 - 27368338
AN - SCOPUS:84976488253
SN - 0340-6717
VL - 135
SP - 1117
EP - 1125
JO - Human Genetics
JF - Human Genetics
IS - 10
ER -