Table 1

Unanswered questions pertaining to intermediate C9orf72 alleles

Minimum C9orf72 repeat length required for neurodegeneration remains unknown
  • Repeat lengths from ≤15 to 27 in the blood have not shown somatic instability in limited studies.56 57

  • TDP43 formation may be ‘age-related’ findings; pathological studies found no expansion or intermediate alleles (20–29 repeats) among LRRK2 G2019S carriers and AD cases with concomitant TDP43-positive inclusions.16

Variation of large-normal and intermediate C9orf72 repeat lengths by ethnicity needs to be determined
  • European haplotype exists in Asian cohorts,25 27 49 but at a lower frequency (<2% in Chinese controls compared with 9% in European controls).25

  • European founder haplotype seen in 15% of Europeans compared with only 0.5% in Asians.49

  • Asian controls appear to carry smaller normal repeat lengths (7–14) compared with Caucasian controls (0–32).38

  • Chinese samples with>12 repeats are rarely observed.25

Effect of homozygosity versus heterozygosity of normal-length and intermediate-length C9orf72 alleles on disease susceptibility
  • Higher methylation levels seen in homozygous intermediate allele carriers compared with homozygous short allele carriers.53

  • No variability in regions flanking the GGGGCC repeat found in pathogenic expansion carriers with second allele repeat size within normal range (2–11).16

  • Homozygous intermediate repeat carriers reported more frequently in FTD compared with controls (6.1% vs 4.6%).51

  • Unanswered questions pertaining to intermediate C9orf72 alleles.

  • FTD, frontotemporal dementia; LRRK2, leucine-rich repeat kinase; TDP43, TAR DNA-binding protein 43.