Clinical and genetic features of somatic mosaicism in facioscapulohumeral dystrophy.
Clinical and genetic features of somatic mosaicism in facioscapulohumeral dystrophy.
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面肩肱营养不良体细胞镶嵌的临床和遗传特征。
DOI：
10.1136/jmedgenet-2019-106638
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发表时间：
2020
影响因子：
4
通讯作者：
Wang Zhiqiang
中科院分区：
文献类型：
--
作者：
Qiu Liangliang;Ye Zhixian;Lin Lin;Wang Lili;Lin Xiaodan;He Junjie;Lin Feng;Xu Guorong;Cai Naiqing;Jin Ming;Chen Haizhu;Lin Minting;Wang Ning;Wang Zhiqiang
目的分析面肩肱营养不良（FSHD）的临床谱、遗传学特征、特异性D4 Z4低甲基化状态和体细胞嵌合现象的基因型-表型相关性。方法这是一项前瞻性、以医院为基础、病例对照、观察性研究，35例FSHD患者招募了10年以上的体细胞嵌合现象，17例外显患者和18例非外显突变携带者。这项研究还包括一个单变量比较17配对马赛克和非马赛克患者FSHD.ResultsMosaic参与者与FSHD不同的诊断年龄（中位数45;范围15-65岁），肌肉力量（FSHD临床评分中位数0;范围0-10分），临床严重程度（年龄校正的临床严重程度评分（ACSS）中位数0;范围0-467分），D4 Z4重复（中位数3;范围2-5个单位），嵌合体比例（中位数55%;范围27%-72%）和D4 Z4甲基化程度（中位数49.82%;范围27.17%-64.51%）。基因型严重程度量表和D4 Z4甲基化程度与ACSS显著相关（p1=0.003; p2=0.002）。在匹配的配对中，17例嵌合体患者的D4 Z4重复序列较短，FSHD临床评分较低，ACSS较低。此外，35名参与者中有34名（97%）携带了两个镶嵌阵列，而一名患者携带了三个镶嵌阵列（3%）。两例还进行了四种类型的非镶嵌阵列染色体10（易位配置）。ConclusionsBroadly，这个大的马赛克FSHD队列表现出显着的临床异质性和相对轻微的疾病严重程度。基因型严重程度量表和D4 Z4低甲基化状态均作为临床表型的修饰因子。与以前的报告一致，有丝分裂染色体间/染色体内基因转换没有交叉，在这里被确定为一个主要的遗传机制下镶嵌FSHD。
PurposeTo analyse the clinical spectrum, genetic features, specific D4Z4 hypomethylation status and genotype–phenotype correlations for somatic mosaicism in facioscapulohumeral dystrophy (FSHD).MethodsThis was a prospective, hospital-based, case–control, observational study of 35 participants with FSHD with somatic mosaicism recruited over 10 years, with 17 penetrant patients and 18 non-penetrant mutation carriers. This study also included a univariate comparison of 17 paired mosaic and non-mosaic patients with FSHD.ResultsMosaic participants with FSHD varied in age of diagnosis (median 45; range 15–65 years), muscle strength (FSHD clinical score median 0; range 0–10 points), clinical severity (age-corrected clinical severity score (ACSS) median 0; range 0–467 points), D4Z4 repeats (median 3; range 2–5 units), mosaic proportion (median 55%; range 27%–72%) and D4Z4 methylation extent (median 49.82%; range 27.17%–64.51%). The genotypic severity scale and D4Z4 methylation extent were significantly associated with ACSS (p1=0.003; p2=0.002). Among the matched pairs, the 17 mosaic patients had shorter D4Z4 repeats, lower FSHD clinical scores and lower ACSS than non-mosaic patients. Additionally, 34 of 35 (97%) participants carried two mosaic arrays, while a single patient had three mosaic arrays (3%). Two cases also carried four-type non-mosaic arrays on chromosome 10 (translocation configuration).ConclusionsBroadly, this large mosaic FSHD cohort exhibited significant clinical heterogeneity and relatively slight disease severity. Both genotypic severity scale and D4Z4 hypomethylation status served as modifiers of clinical phenotypes. Consistent with previous reports, mitotic interchromosomal/intrachromosomal gene conversion without crossover was here identified as a major genetic mechanism underlying mosaic FSHD.