Germ line predisposition variants occur in myelodysplastic syndrome patients of all ages
Germ line predisposition variants occur in myelodysplastic syndrome patients of all ages
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DOI：
10.1182/blood.2022015790
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发表时间：
2022-12-15
期刊：
影响因子：
20.3
通讯作者：
Godley, Lucy A.
中科院分区：
文献类型：
--
作者：
Feurstein, Simone;Trottier, Amy M.;Godley, Lucy A.
在40岁或以下诊断为骨髓增生异常综合征（MDS）的患者中，致病性/可能致病性（P/LP）生殖系变异的频率为15%至20%。然而，目前还没有全面的研究评估这种变异在各个年龄段的频率。我们在异基因造血干细胞移植前对404例MDS患者及其相关供者的外周血样本进行了增强全外显子组测序。分析和解释了233个基因的单核苷酸和拷贝数变异。生殖系状态是通过在患者和相关供体中存在变异来确定的，或者对于那些以前只被视为生殖系等位基因的人。我们在404例MDS患者中的28例（7%）中发现了P/LP生殖系变异，存在于所有年龄十分位数中。P/LP变异的患者比没有变异的患者更有可能发展为高级别MDS （43% vs 25%; P = 0.04）。在有和没有种系变异的患者之间，结果参数没有统计学上的显著差异，但分析不够有力。在年龄小于40岁的患者中发现骨髓衰竭综合征基因的P/LP变异5例，而在年龄大于40岁的患者中发现DDX41 （n = 4）、端粒生物学障碍基因（n = 2）和一般肿瘤易感基因（n = 17）的变异。如果包括假定的种系变异，P/LP变异的产量将增加到11%，并且通过添加未知意义的可疑变异，它将进一步增加到12%。在我们的研究中，高频率的P/LP生殖系变异支持对所有MDS患者进行全面的生殖系基因检测，无论其诊断年龄如何。
The frequency of pathogenic/likely pathogenic (P/LP) germ line variants in patients with myelodysplastic syndrome (MDS) diagnosed at age 40 years or less is 15% to 20%. However, there are no comprehensive studies assessing the frequency of such variants across the age spectrum. We performed augmented whole-exome sequencing of peripheral blood samples from 404 patients with MDS and their related donors before allogeneic hematopoietic stem cell transplantation. Single-nucleotide and copy number variants in 233 genes were analyzed and interpreted. Germ line status was established by the presence of a variant in the patient and related donor or for those seen previously only as germ line alleles. We identified P/LP germ line variants in 28 of 404 patients with MDS (7%), present within all age deciles. Patients with P/LP variants were more likely to develop higher-grade MDS than those without (43% vs 25%; P = .04). There was no statistically significant difference in outcome parameters between patients with and without a germ line variant, but the analysis was underpowered. P/LP variants in bone marrow failure syndrome genes were found in 5 patients aged less than 40 years, whereas variants in DDX41 (n = 4), telomere biology disorder genes (n = 2), and general tumor predisposition genes (n = 17) were found in patients aged more than 40 years. If presumed germ line variants were included, the yield of P/LP variants would increase to 11%, and by adding suspicious variants of unknown significance, it would rise further to 12%. The high frequency of P/LP germ line variants in our study supports comprehensive germ line genetic testing for all patients with MDS regardless of their age at diagnosis.