Genetic report abstractThe CHCHD10 P34S variant is not associated with ALS in a UK cohort of familial and sporadic patients
Introduction
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by lower and upper motor neuron degeneration. Approximately 5%–10% of ALS cases are familial (FALS) with the remainder presenting in a sporadic manner (SALS). Mutations in 4 major genes SOD1, TARDBP, FUS, and the C9orf72 hexanucleotide repeat expansion account for approximately 50% of FALS. A recent report by Bannwarth et al. (2014) described a novel p.Ser59Leu (c.176C>T) mutation in CHCHD10 accounting for ALS and frontotemporal dementia (FTD). Subsequent independent screenings have also confirmed a putative role of CHCHD10 in a broad range of neurodegenerative diseases (Auranen et al., 2015; Johnson et al., 2014; Kurzwelly et al., 2015; Penttila et al., 2015; Zhang et al., 2015) (Supplementary Table 1). Here, we report the first mutation screening of CHCHD10 in a UK cohort of familial and sporadic ALS ± FTD patients.
Section snippets
Methods
All 4 coding exons of CHCHD10 (NM_213720.2) were amplified by polymerase chain reaction and products directly sequenced with an ABI3130 genetic analyzer (Applied Biosystems, Warrington, UK) (Supplementary Data).
Results
Analysis of an existing in-house cohort of 200 UK FALS exomes revealed poor coverage across exon 2 of CHCHD10, a hotspot for reported mutations (only 24.8% of samples met our minimum read depth criteria of 8×). We therefore Sanger sequenced all exons of CHCHD10 in 163 FALS, 262 SALS, and 576 healthy controls to ensure complete coverage of the gene. We identified the previously described p.P34S (c.100C>T) variant in 1 FALS (0.61%), 4 SALS (1.53%), and 8 controls (1.39%). One of these sporadic
Discussion
Our study failed to identify any disease-relevant variants, suggesting that mutations in CHCHD10 are not a common cause in UK ALS ± FTD patients. The p.P34S variant was initially identified in 2 unrelated French ALS-FTD individuals (Chaussenot et al., 2014) and 1 Italian SALS case (Ronchi et al., 2015). However, in an Australian cohort of FTD + ALS and early-onset dementia patients (n = 370), 7 cases as well as 9 aged controls (n = 807) were found to carry the p.P34S change, suggesting that it
Disclosure statement
Christopher E. Shaw and Ammar Al-Chalabi receive salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King's College London. All other authors have no actual or potential conflicts of interest.
Acknowledgements
Funding for this work was provided by The Middlemass family, Heaton-Ellis Trust, Motor Neurone Disease Association, Medical Research Council, the Psychiatry Research Trust of the Institute of Psychiatry, Guy's and St Thomas' Charity, the Wellcome Trust, and the Noreen Murray Foundation. This is an EU Joint Programme—Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND—www.jpnd.eu (United Kingdom, Medical
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2020, Neurobiology of DiseaseCitation Excerpt :Subsequent reports have described other clinical phenotypes including pure ALS and pure FTD, mitochondrial myopathy, and spinal motor neuronopathy (Ajroud-Driss et al., 2015; Dols-Icardo et al., 2015; Jiao et al., 2016; Penttilä et al., 2015; Zhang et al., 2015). Based on mutation frequencies in ethnically matched FTD and ALS cohorts, CHCHD10 mutations appear to be more frequently associated with FTD phenotypes than with pure ALS (Chaussenot et al., 2014; Jiao et al., 2016; Marroquin et al., 2016; Teyssou et al., 2016; Wong et al., 2015). Disease progression in CHCHD10-related FTD and MND/ALS can be markedly slow, lasting up to 40 years (Bannwarth et al., 2014; Müller et al., 2014; Zhang et al., 2015).
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These authors contributed equally to the manuscript.