C9orf72 Repeat Expansion Frequency among Patients with Huntington Disease Genetic Testing.

BACKGROUND

European studies identified the C9orf72 repeat expansion as the most frequent genetic alteration in patients with Huntington disease (HD)-like phenotypes but negative HD genetic testing.

OBJECTIVE

To investigate C9orf72 repeat expansion frequency in individuals tested for HD in a North American tertiary referral laboratory.

METHODS

Three hundred and seventy-three cases (115 positive and 258 negative for HD) were evaluated by genotyping PCR, with follow-up Southern blot and 5' repeat methylation status assessment by combined repeat-primed and methylation-specific PCR in a subset.

RESULTS

Three cases (all HD-negative) tested positive: 2 had > 2,000 repeats and were methylated, 1 had 80-100 repeats and was unmethylated. Two cases (1 HD-positive and 1 HD-negative) had intermediate alleles (20-29 repeats) and were unmethylated. The remaining 368 cases were negative (< 20 repeats). C9orf72 repeat expansion was absent in patients with HD and was identified in a small subset (1.2%) of patients with negative HD genetic testing.

CONCLUSION

These findings suggest that C9orf72 repeat expansion does not coexist with HTT repeat expansion and that C9orf72 repeat expansion testing is unnecessary for patients with HD. In addition, C9orf72 evaluation may be considered for individuals negative for HD genetic testing. Similar to in previous studies, methylation of C9orf72 repeat expansion was limited to large expansions.