The cause of a rare type of familial epilepsy has been linked to two new gene mutations, as discovered by researchers from the Walter and Eliza Hall Institute. Published back-to-back in Nature Communications, Dr Mark Bennett, Dr Haloom Rafehi and Professor Melanie Bahlo from the Institute made this ground-breaking discovery as part of an international consortium.

The effort spanned two decades to identify repeat expansions in the genes STARD7 and MARCH6 that cause two subtypes of a rare epilepsy called Familial Adult Myoclonic Epilepsy (FAME). Repeat expansions are a type of mutation where nucleotides increase in copy number until a certain threshold is crossed, above which they become unstable and cause disease. They are typically associated with neurological diseases, such as Huntington’s disease, autism, and ataxia.

During their efforts, the team developed a new tool to detect repeat expansions in DNA called exSTRA (expanded short tandem repeat algorithm), which has usually been quite difficult to do with typical analytical methods.

FAME has a typical onset in the second to third decade with variable expressivity. The dominant mutations causing this epilepsy are rare. But in affected families, children of affected parents have a 50/50 chance of inheriting the disease. There are four subtypes of FAME: FAME1, FAME2, FAME3 and FAME4. The STARD7 mutation was found to cause FAME2, and MARCH6 to cause FAME3.

The STARD7 mutation causing FAME2 was identified to consist of an ATTTC pentamer expansion within the first intron. All individuals studied with FAME2 had this same expansion.

All patients with the FAME3 subtype were identified to have the same penta-expansion in MARCH6. With the new tool, the team could trace the genetic mutation back to its origin; a European individual with a spontaneous mutation who lived more than 5000 years ago. As well as this, the tool provided valuable information about the pattern of disease spread and showed all affected individuals were distant relatives and very much confined to European populations. This analysis also suggested that MARCH6 repeat expansions are uncommon and unlikely to arise again independently.

The website now published by the researchers allows others to use the tool to discover new mutations and study other genes of interest.

The Walter and Eliza Hall Institute team were supported by the Australian National Health and Medical Research Council and the Victorian Government.