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首页> 外文OA文献 >Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype
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Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype

机译：9q亚端粒缺失综合征的进一步临床和分子鉴定支持EHMT1单倍体不足对核心表型的重大贡献

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BACKGROUND: The 9q subtelomeric deletion syndrome (9qSTDS) is clinically characterised by moderate to severe mental retardation, childhood hypotonia and facial dysmorphisms. In addition, congenital heart defects, urogenital defects, epilepsy and behavioural problems are frequently observed. The syndrome can be either caused by a submicroscopic 9q34.3 deletion or by intragenic EHMT1 mutations leading to haploinsufficiency of the EHMT1 gene. So far it has not been established if and to what extent other genes in the 9q34.3 region contribute to the phenotype observed in deletion cases. This study reports the largest cohort of 9qSTDS cases so far. METHODS AND RESULTS: By a multiplex ligation dependent probe amplification (MLPA) approach, the authors identified and characterised 16 novel submicroscopic 9q deletions. Direct sequence analysis of the EHMT1 gene in 24 patients exhibiting the 9qSTD phenotype without such deletion identified six patients with an intragenic EHMT1 mutation. Five of these mutations predict a premature termination codon whereas one mutation gives rise to an amino acid substitution in a conserved domain of the protein. CONCLUSIONS: The data do not provide any evidence for phenotype-genotype correlations between size of the deletions or type of mutations and severity of clinical features. Therefore, the authors confirm the EHMT1 gene to be the major determinant of the 9qSTDS phenotype. Interestingly, five of six patients who had reached adulthood had developed severe psychiatric pathology, which may indicate that EHMT1 haploinsufficiency is associated with neurodegeneration in addition to neurodevelopmental defect.
机译：背景：9q亚端粒缺失综合征（9qSTDS）在临床上具有中度至重度智力低下，儿童期肌张力低下和面部畸形的特征。此外，经常观察到先天性心脏缺陷，泌尿生殖器缺陷，癫痫和行为问题。该综合征可以由亚显微的9q34.3缺失引起，也可以由导致EHMT1基因单倍缺乏的基因内EHMT1突变引起。到目前为止，尚未确定9q34.3区域中的其他基因是否以及在何种程度上对缺失病例中观察到的表型做出贡献。这项研究报告了迄今为止最大的9qSTDS病例队列。方法和结果：通过多重连接依赖探针扩增（MLPA）方法，作者鉴定并鉴定了16种新的亚显微9q缺失。对24例表现出9qSTD表型而无此缺失的患者进行EHMT1基因的直接序列分析，确定了6例具有基因内EHMT1突变的患者。这些突变中的五个预测了过早的终止密码子，而一个突变在蛋白质的保守域中引起了氨基酸取代。结论：数据没有提供任何证据表明缺失的大小或突变类型与临床特征的严重性之间的表型-基因型相关性。因此，作者确认EHMT1基因是9qSTDS表型的主要决定因素。有趣的是，成年后六名患者中有五名已出现严重的精神病学病理，这可能表明EHMT1单倍功能不全除了神经发育缺陷外还与神经退行性疾病有关。

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