| 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
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| 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
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| 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
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