Table 2

Priorities for research into C9ORF72 intermediate alleles

Address methodological differencesRepeat-primed PCR should be combined with Southern blot for estimation of repeat size and not be used in isolation. Sequencing should be used for smaller repeat sizes.
Deciphering role of DNA composition in expanded repeatsThe ‘critical repeat size’ may not be key, but rather the exact composition within the expanded repeats, including the possibility of repeat interruptions.
Developing novel genotyping methodsDeveloping the ability to conduct a fast comprehensive systematic screen for repeat expansions on a genome-wide level.
Adopting a multigeneration intrafamilial approachPhenotype–genotype correlations within large multigeneration families can minimise the effect of heterogeneity in genetic background and confounders.
Detailed clinical phenotypingDetailed clinical and neuropsychological profiling in symptomatic and asymptomatic carriers and healthy controls for accurate genotype–phenotype correlations.
Developing better cellular models of C9orf72Patient-derived induced pluripotent stem cell neurons harbouring different repeat sizes and transgenic non-human primates can provide additional insights.
Longitudinal cohort studyA longitudinal cohort including subjects with intermediate alleles with long-term follow-up supported by detailed clinical, neuroimaging and biochemical evaluation.
Multicentre study approach for optimising sample sizeA global multicentre approach with standardised protocols and a centralised genotyping laboratory will aid in identifying rare associations, elucidate variation according to ethnicity and minimise diagnostic errors.