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首页> 外文期刊>Balkan journal of medical genetics: BJMG >Clinical next generation sequencing reveals an H3F3A gene as a new potential gene candidate for microcephaly associated with severe developmental delay, intellectual disability and growth retardation
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Clinical next generation sequencing reveals an H3F3A gene as a new potential gene candidate for microcephaly associated with severe developmental delay, intellectual disability and growth retardation

机译：临床下一代测序揭示了H3F3A基因，作为与严重发育延迟，智力残疾和生长迟缓相关的微孢子的新潜在基因候选者

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Microcephaly is characterized by significant clinical and genetic heterogeneity, therefore reaching the genetic diagnosis remains challenging in this group of disorders. We describe a case of a girl with secondary microcephaly, associated with severe developmental delay, intellectual disability, growth retardation and dysmorphic features. For purposes of clinical genetic diagnostic testing, we performed trio whole exome sequencing in the proband and unaffected parents. We found a heterozygous de novo missense variant in the H3F3A gene in the proband (NM_ 002107.4: c.185TG), which is absent from the gnomAD and from the Slovenian Genome databases. The identified variant affects a highly conserved leucine residue at position 62 of the histone H3 protein (H3.3) and is predicted to affect the physicochemical properties of the affected protein. Mouse models, which demonstrated involvement of H3.3 protein in the control of neuronal- and glial-specific gene expression patterns that control synaptic connectivity and behavioral plasticity. Additionally, we also identified similar cases reported in the ClinVar database. These arguments support the possible pathogenic role of the reported genetic variant and thus suggest a novel molecular mechanism for this syndromic form of microcephaly.
机译：微头特征在于显着的临床和遗传异质性，因此达到遗传诊断在这组疾病中仍然具有挑战性。我们描述了一个患有次微生谱的女孩的病例，与严重发育延迟相关，智力残疾，生长延迟和疑似特征。出于临床遗传诊断测试的目的，我们在证据和未受影响的父母中进行了三中的全稀有序列。我们发现了一种杂合的De Novo畸形变体在H3F3A基因中的证书（NM_ 002107.4：C.185T> G）中，其从Gnomad和斯洛文尼亚基因组数据库中不存在。所鉴定的变体影响组蛋白H3蛋白（H3.3）的位置62处的高度保守的亮氨酸残基，预计会影响受影响蛋白的物理化学特性。小鼠模型，其展示了H3.3蛋白在控制突触连通性和行为可塑性的神经元和胶质特异性基因表达模式中的控制。此外，我们还确定了Clinvar数据库中报告的类似案例。这些争论支持报告的遗传变异的可能致病作用，因此表明了这种综合征形式的微微畸形的新的分子机制。

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