AUTHOR=Tang Lu , Chen Lu , Liu Xiaolu , He Ji , Ma Yan , Zhang Nan , Fan Dongsheng 

TITLE=The repeat length of C9orf72 is associated with the survival of amyotrophic lateral sclerosis patients without C9orf72 pathological expansions

JOURNAL=Frontiers in Neurology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2022.939775

DOI=10.3389/fneur.2022.939775

ISSN=1664-2295

ABSTRACT=<sec><title>Objective</title><p>To explore whether the repeat lengths of the chromosome 9 open reading frame 72 (<italic>C9orf72</italic>) gene and the ataxin-2 (<italic>ATXN2</italic>) gene in amyotrophic lateral sclerosis (ALS) patients without <italic>C9orf72</italic> repeat expansions confer a risk of ALS or survival disadvantages in ALS.</p></sec><sec><title>Methods</title><p>We screened a hospital-based cohort of Chinese patients with sporadic ALS without <italic>C9orf72</italic> repeat expansions and neurologically healthy controls for <italic>C9orf72</italic> GGGGCC and <italic>AXTN2</italic> CAG repeat length to compare the frequency of possible detrimental length alleles using several thresholds. Furthermore, the clinical features of ALS were compared between patients with ALS subgroups using different length thresholds of maximum <italic>C9orf72</italic> and <italic>ATXN2</italic> repeat alleles, such as sex, age of onset, diagnostic delay, and survival.</p></sec><sec><title>Results</title><p>Overall, 879 sporadic patients with ALS and 535 controls were included and the repeat lengths of the <italic>C9orf72</italic> and <italic>ATXN2</italic> were both detected. We found significant survival differences in patients using a series of <italic>C9orf72</italic> repeat length thresholds from 2 to 5, among which the most significant difference was at the cutoff value of 2 (repeats 2 vs. &gt;2: median survival 67 vs. 55 months, log-rank <italic>p</italic> = 0.032). Furthermore, Cox regression analysis revealed the role of age of onset [hazard ratio (HR) 1.04, 95% CI 1.03–1.05, <italic>p</italic> &lt; 0.001], diagnostic delay (0.95, 0.94–0.96, <italic>p</italic> &lt; 0.001), and carrying <italic>C9orf72</italic> repeat length of 2 (0.72, 0.59–0.89, <italic>p</italic> = 0.002) in the survival of patients without <italic>C9orf72</italic> repeat expansions. In addition, bulbar onset was associated with poorer survival when the patients carried the maximum <italic>C9orf72</italic> repeat allele over 2 (1.81, 1.32–2.48, <italic>p</italic> &lt; 0.001). However, no survival difference was found when applying a series of continuous cutoff values of <italic>ATXN2</italic> or stratified by <italic>C9orf72</italic> repeats of 2.</p></sec><sec><title>Conclusion</title><p>The length of 2 in the maximum <italic>C9orf72</italic> repeat allele was identified to be associated with favorable survival in ALS patients without <italic>C9orf72</italic> repeat expansions. Our findings from the clinical setting implicated the possible cutoff definition of detrimental C9orf72 repeats, which should be helpful in the understanding of genetics in ALS and in clinical genetic counseling.</p></sec>