Abstract
Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.
Highlights
Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures
TTTCA repeats in SAMD12 on chromosome 8q24 have been identified as the main cause of FAME1 (BAFME1) in the Japanese and Chinese populations[8,9,10,11]
We present evidence that FAME3 results from repeat expansions similar to those described in SAMD12 for
Summary
Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. AME is an autosomal dominant, very slowly progressive condition characterized by cortical tremor affecting mainly the hands, frequently associated with generalized myoclonic and sometimes tonic-clonic seizures, and, more rarely, focal seizures[1,2,3]. This condition was first described in Japan as benign adult familial myoclonic epilepsy (BAFME), and subsequently referred to as familial cortical myoclonic tremor with epilepsy (FCMTE) or autosomal dominant cortical myoclonus and epilepsy (ADCME). Parallel research in a large Dutch FAME pedigree (Family 3; Fig. 1c) linked to the same region on chr5p had revealed a missense variant
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
