Mutation spectrum and genotype-phenotype correlations in a large French cohort of MYH9-Related Disorders.
Mutation spectrum and genotype-phenotype correlations in a large French cohort of MYH9-Related Disorders.
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DOI：
10.1002/mgg3.68
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发表时间：
2014-07
影响因子：
2
通讯作者：
Schlegel, Nicole
中科院分区：
文献类型：
--
作者：
Saposnik, Beatrice;Binard, Sylvie;Fenneteau, Odile;Nurden, Alan;Nurden, Paquita;Hurtaud-Roux, Marie-Francoise;Schlegel, Nicole
MYH 9相关疾病是一组罕见的常染色体显性血小板疾病，表现为以巨血小板减少症伴巨大血小板和白细胞包涵体为特征的非综合征形式，或表现为这些血液学特征与耳聋和/或肾病和/或白内障相结合的综合征形式。它们是由编码非肌肉肌球蛋白重链II-A（NMMHC-IIA）的MYH 9基因突变引起的。到目前为止，至少有49个MYH 9突变在孤立病例或小系列中报告，但在大系列中很少。我们报告了一项对来自37例散发病例和39个无关家族的109例患者进行的为期8年的大型队列研究结果。我们已经确定了43种遗传变异，其中21种对我们的患者来说是新的。大多数，33（76.7%），是错义突变和6个外显子优先靶向，如先前公布的。其他改变是三个一个核苷酸的缺失，一个更大的21个核苷酸的缺失，和一个重复。在内含子40的供体剪接位点上首次发现了T>A的替换（c.5765+ 2 T>A）。7名患者，其中4名来自同一个家庭，有两种遗传变异。基因型-表型关系的分析使我们能够提高对这种异质性但重要的罕见疾病的认识。
MYH9-Related Disorders are a group of rare autosomal dominant platelet disorders presenting as nonsyndromic forms characterized by macrothrombocytopenia with giant platelets and leukocyte inclusion bodies or as syndromic forms combining these hematological features with deafness and/or nephropathy and/or cataracts. They are caused by mutations in the MYH9 gene encoding the nonmuscle myosin heavy chain II-A (NMMHC-IIA). Until now, at least 49 MYH9 mutations have been reported in isolated cases or small series but only rarely in large series. We report the results of an 8-year study of a large cohort of 109 patients from 37 sporadic cases and 39 unrelated families. We have identified 43 genetic variants, 21 of which are novel to our patients. A majority, 33 (76.7%), were missense mutations and six exons were preferentially targeted, as previously published. The other alterations were three deletions of one nucleotide, one larger deletion of 21 nucleotides, and one duplication. For the first time, a substitution T>A was found in the donor splice site of intron 40 (c.5765+2T>A). Seven patients, four from the same family, had two genetic variants. The analysis of the genotype-phenotype relationships enabled us to improve the knowledge of this heterogeneous but important rare disease.