Repeat Expansions with Small TTTCA Insertions in MARCHF6 Cause Familial Myoclonus without Epilepsy

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Familial adult myoclonus epilepsy (FAME) is a rare autosomal dominant disorder.
• Pathogenic FAME mutations involve intronic repeat expansions (TTTTA/TTTCA) in specific genes.
• TTTCA repeat insertions are pathogenic, while TTTTA-only expansions are benign.

Purpose of the Study:

• Investigate the genetic cause of dominant cortical myoclonus without seizures in two families.
• Identify novel genetic variants associated with this neurological disorder.

Main Methods:

• Utilized repeat-primed PCR, long-range PCR, and nanopore sequencing.
• Analyzed known FAME loci for repeat expansions.
• Characterized the identified genetic variants.

Main Results:

• Discovered a new repeat expansion in the MARCHF6 gene in 8 affected individuals.
• The expansion consists of 388-454 TTTTA repeats and 5-11 TTTCA repeats.
• Observed meiotic stability with low somatic variability and an inverse correlation between TTTCA repeat number and myoclonus onset age.

Conclusions:

• As few as five TTTCA repeats, alongside expanded TTTTA repeats, can cause cortical myoclonus without epilepsy.
• These findings elucidate potential mechanisms in FAME pathophysiology.
• Highlights the role of specific repeat configurations in disease manifestation.