This work is presented on behalf of The FAME Consortium.
Dynamic mutations are pathogenic expansions of short tandem repeat sequences and are frequently associated with disorders of movement. In most cases, families affected by these mutations show anticipation in the form of increasing symptom severity and / or decreased age of onset. Familial adult myoclonic epilepsy (FAME) is characterised by cortical myoclonic tremor usually in the second decade of life with later onset of myoclonic and generalised tonic clinic seizures. There are four loci identified through linkage implicated in FAME that are located on chromosomes (chr) 2, 3, 5 and 8. Expansion of an endogenous ATTTT pentameter coupled with insertion and expansion of an ATTTC pentamer within the SAMD12 gene are the cause of FAME at the chr8 locus and also two new FAME genes RAPGEF2 on chr4 and TNRC6A on chr16. Using both long and short read whole genome sequencing, repeat primed PCR and Southern blotting we show that FAME linked to chr2 is caused by a similar dynamic mutation of the same pentanucleotide repeats that arise in the first intron of the STARD7 gene. The ATTTC expansion was found to segregate with disease or obligate carrier status in over 250 individuals from all 22 families that we tested including those with previously identified damaging variants in ADRA2B. RNA-Seq from patient derived fibroblast cell lines showed no accumulation of the AUUUU or AUUUC repeat sequences however a significant enrichment of differentially expressed genes implicated in lysosomal storage disorders and progressive myoclonic epilepsy suggested that molecular pathways involved in cellular garbage collection were active. Our data strongly support that regardless of the linked interval, ATTTC expansions are a general cause of FAME and are predicted to affect thousands of individuals worldwide.