Frequency of the C9ORF72 hexanucleotide repeat expansion in ALS and FTD in diverse populations: a cross-sectional study
By E. Majounie, A. Renton, K. Mok, E. Dopper, A. Waite, S. Rollinson, A. Chiò, G. Restagno, N. Nicolaou, J. Simón-Sánchez and 49 more. Lancet Neurology, 2012
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Background A hexanucleotide repeat expansion in the C9ORF72 gene has recently been shown to cause a large proportion of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). Methods We screened 4,448 patients diagnosed with ALS and 1,425 patients diagnosed with FTD drawn from diverse populations for the hexanucleotide expansion using a repeat-primed PCR assay. ALS and FTD were diagnosed according to the El Escorial and Lund-Manchester criteria respectively. Familial status was based on self-reported family history of similar neurodegenerative diseases at the time of sample collection. Haplotype data of 262 patients carrying the expansion were compared with the known Finnish founder risk haplotype across the chromosomal locus. Age-related penetrance was calculated by the Kaplan-Meier method using data from 603 individuals carrying the expansion. Findings The mutation was observed among 7·0% (n = 236 of 3,377) of Caucasians, 4·1% (n = 2 of 49) of African-Americans, and 8·3% (n = 6 of 72) of Hispanic individuals diagnosed with sporadic ALS, whereas the rate was 6·0% (n = 59 of 981) among Caucasians diagnosed with sporadic FTD. Among Asians, 5·0% (n = 1 of 20) of familial ALS and 66·6% (n = 2 of 3) of familial FTD cases carried the repeat expansion. In contrast, mutations were not observed among patients of Native American (n = 3 sporadic ALS), Indian (n = 31 sporadic ALS, n = 31 sporadic FTD), and Pacific Islander (n = 90 sporadic ALS) ethnicity. All patients with the repeat expansion carried, either partially or fully, the founder haplotype suggesting that the expansion occurred on a single occasion in the past (~1,500 years ago). The pathogenic expansion was non-penetrant below 35 years of age, increasing to 50·0% penetrance by 58 years of age, and was almost fully penetrant by 80 years of age. Interpretation We confirm that a common single Mendelian genetic lesion is implicated in a large proportion of sporadic and familial ALS and FTD. Testing for this pathogenic expansion will be important in the management and genetic counseling of patients with these fatal neurodegenerative diseases. Funding See Acknowledgements.
Subfields: Cellular and Molecular Neuroscience, Genetics, Neurology
View Paper: https://www.semanticscholar.org/paper/6e90aa21dac978b25ba56e1f4b18318a30fc69fc
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Citations in the corpus
- A comprehensive review of amyotrophic lateral sclerosis (2015, background): “[73,239,308] The additional genes that are known to cause FALS include: TARDBP, encodes TAR DNAbinding protein 43 (TDP-43); FUS, which codes for fusion in sarcoma; ANG, which codes for angiogenin, ribonuclease, and the RNAase A family 5; OPTN, which codes for optineurin; and C9orf72.[23,49,56,100,13”
- RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention (2013, positive): “…discovered hexanucleotide ''GGGGCC'' repeat'' expansion in the noncoding region of the C9ORF72 gene has been found in at least 8% of sporadic ALS (sALS) and FTD cases and more than 40% of familial ALS (FALS) and FTD cases (DeJesus-Hernandez et al., 2011; Majounie et al., 2012; Renton et al., 2011).”