FAME3_MARCHF6
- Gene
- MARCHF6
- Disease
- FAME3
- Inheritance
- AD
- Classification
- Definitive
- Total Score
- 11.5
- Publications Reviewed
- 3
- Publication Span
- 17.33 years
- Last Updated
- 08/12/2025
- Curator(s)
- Macayla Weiner, Laurel Hiatt, Harriet Dashnow
Description
Autosomal dominant familial adult myoclonic epilepsy type 3 (FAME3) is associated with an intronic TTTTA/TTTCA repeat expansion in MARCH6/MARCHF6 on chromosome 5p15.2. The expansion was identified by genome sequencing and repeat-primed PCR in four European families with cortical/myoclonic tremor and epilepsy, co-segregated with disease, and was absent from controls in the reported analyses. Expansion length, particularly the TTTCA component, inversely correlated with age at seizure onset. Patient-derived blood cells and fibroblasts showed marked somatic instability and expansion-size variability.
Genetic evidence
Total: 10
| Singular Evidence | Probands | PMID:31664039 | 1.5 | MARCH6/MARCHF6 intronic TTTTA/TTTCA expansions identified in four European FAME families (two French, one Dutch, one German) using genome sequencing and RP-PCR. |
| Collective Evidence | Allele | PMID:31664039 | 1 | Expansion length, mainly the TTTCA component, inversely correlated with age at seizure onset; no significant correlation was observed with tremor onset. |
| Collective Evidence | Segregation | PMID:31664039 | 1.5 | 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. |
| Collective Evidence | Segregation | PMID:12140665 PMID:19616813 | 0 | 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. |
| Statistics | Case-control data | PMID:31664039 | 6 | 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. |
Experimental evidence
Total: 1.5
| Function | Regulatory impact | PMID:31664039 | 0.5 | 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. |
| Functional Alteration | Patient cells | PMID:31664039 | 1 | Patient-derived blood cells and fibroblasts showed extensive somatic instability, multiple expansion configurations, and micro-rearrangements in individuals with the largest MARCH6 expansions. |
Note: Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.