Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium.
Neurology. 2010 Jul 6;75(1):72-6. doi: 10.1212/WNL.0b013e3181e62088. Epub 2010 May 19.
The aim of this study was to determine the genetic defect in a 4-generational family with an epileptic disorder characterized by febrile and afebrile polymorphic seizures and mild to severe mental retardation by means of analyzing the neuronal voltage-gated sodium channel alpha-subunit gene SCN1A for mutations.
A Bulgarian family was ascertained and clinically assessed, followed by mutation analysis of the SCN1A gene using direct sequencing to detect point mutations and multiplex amplicon quantification to identify copy number variations.
A microdeletion encompassing the entire SCN1A gene segregating with all affected members was identified in this family. Additional analysis showed that the unaffected father of the proband is mosaic for the deletion. So far, SCN1A deletions, predicted to lead to haploinsufficiency, are exclusively identified in isolated patients with Dravet or contiguous gene syndromes. Because of the severe phenotype, SCN1A deletion carriers are usually not able to live independently and start a family, and hence do not transmit the disease.
We report an inherited SCN1A gene deletion not exclusively associated with Dravet syndrome. Moreover, our results demonstrate that SCN1A haploinsufficiency can cause a significant intrafamilial clinical variability including moderately affected to syndromal patients. The involvement of multiple genetic and environmental factors could be the basis of this difference in phenotype severity.
本研究旨在通过分析神经元电压门控钠通道α亚单位基因 SCN1A 的突变，确定一个具有热性和无热性多态性癫痫发作以及轻度至重度智力障碍的 4 代家族的遗传缺陷。
确定一个保加利亚家族并进行临床评估，然后使用直接测序对 SCN1A 基因进行突变分析，以检测点突变，并使用多重扩增子定量分析来识别拷贝数变异。
在这个家族中发现了一个包含整个 SCN1A 基因的微缺失，该缺失与所有受影响的成员一起遗传。进一步的分析表明，先证者未受影响的父亲是该缺失的嵌合体。到目前为止，SCN1A 缺失被预测为导致单倍不足，仅在孤立的患有 Dravet 或连续基因综合征的患者中被识别。由于严重的表型，SCN1A 缺失携带者通常无法独立生活并组建家庭，因此不会传播疾病。
我们报告了一种遗传性 SCN1A 基因缺失，它不仅与 Dravet 综合征有关。此外，我们的结果表明，SCN1A 单倍不足可能导致明显的家族内临床变异性，包括中度受影响至综合征患者。多个遗传和环境因素的参与可能是表型严重程度差异的基础。
