CHCHD10 variants in amyotrophic lateral sclerosis: Where is the evidence?
CHCHD10 variants in amyotrophic lateral sclerosis: Where is the evidence?
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DOI：
10.1002/ana.25273
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发表时间：
2018-07
影响因子：
11.2
通讯作者：
Project MinE ALS Sequencing Consortium
中科院分区：
文献类型：
--
作者：
Project MinE ALS Sequencing Consortium
自从首次报道具有类似肌萎缩侧索硬化症(ALS)特征的线粒体疾病的CHCHD10突变后，CHCHD10突变被认为是ALS的常见原因。然而，这些突变的确切致病性和临床意义仍不清楚。在这里，我们的目标是确定CHCHD10突变在ALS中的作用。我们分析了来自7个不同国家的4,365名ALS患者和1,832名对照的全基因组序列，并检查了CHCHD10中所有非同义的单核苷酸变异(SNV)。使用几种遗传负担测试(包括SKAT、SKAT-O和Firth Logistic回归)，对这些因素与ALS的相关性进行了独立和综合测试。我们在病例中发现了三个新的变种，但只有一个是ALS特有的。此外，还发现了一个对照特有的突变。与对照组相比，ALS患者中罕见编码突变的负担没有增加(SKAT、SKAT-O和Firth分别为P=0.86、P=0.86和P=0.88)。少数具有潜在致病基因CHCHD10突变的携带者表现出缓慢进展的ALS样表型，具有非典型特征，如肌病和耳聋。CHCHD10突变似乎不是单纯ALS的常见原因，而是与更复杂的表型有关。似乎没有足够的证据证明之前报道的大多数纯性肌萎缩侧索硬化症变异的致病性。这项研究表明，不推荐在纯ALS中进行CHCHD10突变的常规检测，并说明了充分的遗传和功能证据在确定遗传变异的致病性方面的重要性。
After the initial report of a CHCHD10 mutation in mitochondrial disease with features resembling amyotrophic lateral sclerosis (ALS), CHCHD10 mutations have been considered to be a frequent cause for ALS. However, the exact pathogenicity and clinical significance of these mutations remain unclear. Here, we aimed to determine the role of CHCHD10 mutations in ALS. We analyzed 4,365 whole-genome sequenced ALS patients and 1,832 controls from 7 different countries and examined all non-synonymous single nucleotide variants (SNVs) in CHCHD10. These were tested for association with ALS, independently and in aggregate using several genetic burden tests (including SKAT, SKAT-O and Firth logistic regression). We identified three new variants in cases, but only one was ALS-specific. Also, one control-specific mutation was identified. There was no increased burden of rare coding mutations among ALS patients compared to controls (P = 0.86, P = 0.86 and P = 0.88 for SKAT, SKAT-O and Firth, respectively). The few carriers with potential pathogenic CHCHD10 mutations exhibited a slowly progressive ALS-like phenotype with atypical features such as myopathy and deafness. CHCHD10 mutations seem to be a far less prevalent cause of pure ALS than previously suggested, and instead appear related to more complex phenotypes. There appears to be insufficient evidence for the pathogenicity of most previously reported variants in pure ALS. This study shows that routine testing for CHCHD10 mutations in pure ALS is not recommended and illustrates the importance of sufficient genetic and functional evidence in establishing pathogenicity of genetic variants.
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影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
Cunningham F
影响因子：
11.1
作者：
Genin EC;Plutino M;Bannwarth S;Villa E;Cisneros-Barroso E;Roy M;Ortega-Vila B;Fragaki K;Lespinasse F;Pinero-Martos E;Augé G;Moore D;Burté F;Lacas-Gervais S;Kageyama Y;Itoh K;Yu-Wai-Man P;Sesaki H;Ricci JE;Vives-Bauza C;Paquis-Flucklinger V
通讯作者：
Paquis-Flucklinger V
影响因子：
30.8
作者：
Francioli, Laurent C.;Menelaou, Andronild;Wijmenga, Cisca
通讯作者：
Wijmenga, Cisca
影响因子：
5.8
作者：
Raczy, Come;Petrovski, Roman;Tanner, Stephen W.
通讯作者：
Tanner, Stephen W.
影响因子：
11.2
作者：
Penttila, Sini;Jokela, Manu;Udd, Bjarne
通讯作者：
Udd, Bjarne