Genetic reports abstractNegative resultsScreening for C9orf72 repeat expansions in Chinese amyotrophic lateral sclerosis patients
Introduction
Amyotrophic lateral sclerosis (ALS) is a syndrome characterized by progressive deterioration involving the corticospinal tract, brainstem, and anterior horn cells of the spinal cord. Although most cases are sporadic (sALS), approximately 5%–10% of ALS patients have a positive family history (fALS) and show a Mendelian pattern of inheritance (Chio et al., 2008). Mutations in the Cu/Zn superoxide dismutase gene (SOD1) was the most common known genetic cause, accounting for up to 20% of fALS and approximately 2% of sALS (Rosen et al., 1993). Recently, patients with ALS, frontotemporal dementia (FTD), or ALS-FTD, were found to carry 700–1600 copies of GGGGCC hexanucleotide repeat expansions in the noncoding region of the C9orf72 gene, compared with up to 23 copies in normal individuals (DeJesus-Hernandez et al., 2011; Renton et al., 2011). In white populations, mutations in C9orf72 account for 23.5%–46.4% of fALS and 4.1%–21.0% of sALS, and therefore, exceed mutations in SOD1, and become the most frequent cause of ALS (DeJesus-Hernandez et al., 2011; Gijselinck et al., 2012; Majounie et al., 2012; Renton et al., 2011). To our knowledge, analysis of C9orf72 mutations in Chinese ALS patients has only been performed in 2 studies (Garcia-Redondo et al., 2012; Tsai et al., 2012). To investigate the frequency of C9orf72 mutations further, we screened a cohort of Chinese patients including fALS and sALS cases for C9orf72 repeat expansions.
Section snippets
Methods
To determine the presence of abnormal GGGGCC hexanucleotide repeat expansions within the C9orf72 gene, a fluorescent repeat-primed polymerase chain reaction assay was performed as reported previously (Renton et al., 2011) in 20 fALS indexes, 324 sALS patients, and 245 healthy control subjects (full methods available in Supplementary data).
Results
No abnormal repeat expansions were identified in either ALS patients or healthy control samples. The distribution of the estimated repeat numbers for both groups are shown in Supplementary Fig. 1.
Discussion
The recent discovery of C9orf72 gene mutation as a cause of ALS and/or FTD has led to comprehensive genetic analysis of this mutation in ALS patients from different geographic regions. Surprisingly, the frequency of C9orf72 repeat expansions varies greatly across populations. In white populations, it ranges from 46% of fALS and 21% of sALS in Finnish to 22% of fALS and 5% of sALS in German, with intermediate frequencies in other European and white American populations (Garcia-Redondo et al.,
Disclosure statement
The authors do not have any actual or potential conflicts of interest.
Acknowledgements
The authors thank the patients and their families, and the healthy control subjects, for their cooperation in this study. The authors also thank Dr Yi-Chung Lee and Dr Ching-Paio Tsai for kindly performing the repeat-primed polymerase chain reaction for the fALS indexes to confirm the results, Dr Henry Houlden for kindly providing the positive control DNA sample of the C9orf72 hexanucleotide repeat expansion, and Dr Alan E. Renton for technical advice. This study was funded by the National