Curation FAME3 MARCHF6

MARCH6/MARCHF6 intronic TTTTA/TTTCA expansions identified in four European FAME families (two French, one Dutch, one German) using genome sequencing and RP-PCR.

Expansion length, mainly the TTTCA component, inversely correlated with age at seizure onset; no significant correlation was observed with tremor onset.

The MARCH6 expansion co-segregated with FAME in the reported families, including Dutch Family 3 where an incompletely segregating CTNND2 variant was reclassified as likely benign.

Large multigenerational families with FCMTE/FCTE show clear autosomal dominant segregation of the phenotype; however, linkage analyses excluded known loci (8q23.3-q24.1 and 2p11.1-q12.2), indicating genetic heterogeneity. These studies support heritable segregation of disease but do not demonstrate segregation of the MARCH6 repeat expansion specifically.

MARCH6 expansions were identified in affected FAME families, while 83 European controls showed only 9-20 TTTTA repeats and no larger or TTTCA-containing alleles.

RNA-seq and qRT-PCR in expansion-carrier blood cells and fibroblasts found no detectable change in MARCH6 RNA or protein levels and no massive intron 1 retention/splicing abnormality.

Patient-derived blood cells and fibroblasts showed extensive somatic instability, multiple expansion configurations, and micro-rearrangements in individuals with the largest MARCH6 expansions.