The phenotypic spectrum of ARHGEF9 includes intellectual disability, focal epilepsy and febrile seizures
The phenotypic spectrum of ARHGEF9 includes intellectual disability, focal epilepsy and febrile seizures
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DOI：
10.1007/s00415-017-8539-3
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发表时间：
2017-07-01
影响因子：
6
通讯作者：
Afawi, Zaid
中科院分区：
文献类型：
--
作者：
Klein, Karl Martin;Pendziwiat, Manuela;Afawi, Zaid
X染色体基因ARHGEF 9的突变或结构基因组改变已在男性和女性智力残疾患者中描述。观察到不同程度的过度兴奋和癫痫，但描述不完全。在这里，我们扩大了ARHGEF 9的表型谱，通过描述一个大的埃塞俄比亚犹太家庭癫痫和智力残疾。招募了四名受影响的男性兄弟姐妹，他们未受影响的父母和两名未受影响的女性兄弟姐妹并进行表型分析。使用SNP微阵列进行参数连锁分析。通过桑格测序证实了两个受影响个体的外显子组测序的变体。所有受影响的男性兄弟姐妹从2-3岁开始有热性惊厥和智力残疾。3例在7-17岁之间发生无热性惊厥。3例出现局灶性癫痫症状。无一人有过度兴奋。一种新的ARHGEF 9变体（c.967G > A，p.G323R，NM_015185.2）在所有受影响的男性同胞中是半合子的，在母亲中是杂合子的。该家族揭示了ARHGEF 9的表型谱比通常假设的更广，包括在不存在过度兴奋或其他临床显著特征的情况下的伴智力残疾的热性惊厥和局灶性癫痫。我们的研究结果表明，ARHGEF 9的致病性变异可能比以前认为的在智力残疾和轻度癫痫患者中更常见。
Mutations or structural genomic alterations of the X-chromosomal gene ARHGEF9 have been described in male and female patients with intellectual disability. Hyperekplexia and epilepsy were observed to a variable degree, but incompletely described. Here, we expand the phenotypic spectrum of ARHGEF9 by describing a large Ethiopian-Jewish family with epilepsy and intellectual disability. The four affected male siblings, their unaffected parents and two unaffected female siblings were recruited and phenotyped. Parametric linkage analysis was performed using SNP microarrays. Variants from exome sequencing in two affected individuals were confirmed by Sanger sequencing. All affected male siblings had febrile seizures from age 2-3 years and intellectual disability. Three developed afebrile seizures between age 7-17 years. Three showed focal seizure semiology. None had hyperekplexia. A novel ARHGEF9 variant (c.967G > A, p.G323R, NM_015185.2) was hemizygous in all affected male siblings and heterozygous in the mother. This family reveals that the phenotypic spectrum of ARHGEF9 is broader than commonly assumed and includes febrile seizures and focal epilepsy with intellectual disability in the absence of hyperekplexia or other clinically distinguishing features. Our findings suggest that pathogenic variants in ARHGEF9 may be more common than previously assumed in patients with intellectual disability and mild epilepsy.