Benign adult familial myoclonic epilepsy (BAFME): evidence of an extended founder haplotype on chromosome 2p11.1-q12.2 in five Italian families

Abstract

Benign adult familial myoclonic epilepsy (BAFME or FAME) is an autosomal dominant condition, characterized by shivering-like tremors of cortical origin, myoclonus, and epilepsy. Linkage to chromosomes 2p11.1-q12.2 and 8q23.1-q24.11 has been reported in Japanese and Italian families, respectively. We aimed to determine whether a common founder haplotype was shared by five BAFME families from southern Italy and attempted preliminary genotype-phenotype correlation analyses. Five Italian BAFME families were identified. One family has not been previously reported. DNA from 53 affected individuals was genotyped with highly polymorphic microsatellite markers spanning chromosomes 2p11.1-q12.2 and 8q23.1-q24.11. Multipoint linkage analysis was performed using LINKMAP 5.1 software assuming an autosomal dominant trait with 0.99 penetrance and frequency of 0.001. Significant linkage was found on chromosome 2p11.1-q12.2 and a maximum cumulative lod score of 18.5 was found for markers D2S2161 and D2S388. The haplotype "5332" of adjacent markers D2S388, D2S2216, D2S113, and D2S2175 segregates with the disease in all families indicating that the same mutation inherited from a common ancestor segregates in these families. Preliminary genotype-phenotype showed that patients carrying the disease haplotype show minor clinical differences, suggesting that expressivity of the founder mutation is not markedly influenced by other factors. The identification of causative mutations in BAFME requires an extensive and collaborative screening effort.

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

“…1, wedged y-axis labels), suggesting relatedness of these four Italian families through a common ancestor. All four families are either from, or reside in close proximity to, Naples, Italy, and this result is consistent with the previous findings of a shared haplotype between Neapolitan families by identity by the state analysis using microsatellite data (N = 4 markers) (Madia et al 2008;Licchetta et al 2013). Relatedness between these families suggests that the same causal variant should be responsible for the FAME disorder in these cases.…”

“…Subsequent to this, using hg19 coordinates, the FAME2 critical region was refined several times to the most recent interval of 10.4 Mb spanning markers D2S2216 and D2S2175 within 2p11.2-q11.2 (Fig. 1, dotted vertical lines) (Madia et al 2008;Saint-Martin et al 2008;Crompton et al 2012;Licchetta et al 2013). Combining our IBD region with the most resent FAME2 interval further shortens the FAME2 critical region to 9.78 Mb region spanning markers rs10179529 and D2S2175 within 2p11.2-q11.2 and containing 53 RefSeq genes (https://genome.ucsc.…”

“…A founder effect has been proposed for six families, residing within close proximity in Italy, that have been mapped to the FAME2 locus and have a likely, identical microsatellite marker-based haplotype segregating in all families (Madia et al 2008;Licchetta et al 2013). However, the identification of a pathogenic variant has been unsuccessful so far.…”

“…Guerrini et al (2001) performed a genomic analysis and identified a second disease locus (FAME2) on chromosome 2. Following this, multiple European families with FAME characteristics have been described and the FAME2 locus was refined to a 10.4 Mb region spanning chromosome 2p11.1-q12.2 and containing 61 RefSeq genes (Madia et al 2008;Saint-Martin et al 2008;Crompton et al 2012;Licchetta et al 2013). de Fusco et al (2014) sequenced candidate genes within the FAME2 locus and identified a novel in-frame insertion/ deletion in the ADRA2B gene potentially causal for the disorder in two families from Tuscany, Italy.…”

Autosomal dominant cortical tremor, myoclonus, and epilepsy: is the origin in the cerebellum? Editorial

“…Over the past decade, several European kindreds with overlapping clinical features have been reported under different acronyms, such as autosomal dominant cortical myoclonus and epilepsy and familial cortical myoclonic tremor with epilepsy (FCMTE) [4][5][6][7]. The available literature now suggests a worldwide distribution (more than 60 families have been reported) and genetic heterogeneity, yet with evidence that 2p11.1-q12.2 is a major locus for the kindreds of European origin [8]. Most affected individuals experience tonic-clonic seizures, which begin later than "tremor."…”