Microdeletions in 9q33.3-q34.11 in five patients with intellectual disability, microcephaly, and seizures of incomplete penetrance: is STXBP1 not the only causative gene?
Microdeletions in 9q33.3-q34.11 in five patients with intellectual disability, microcephaly, and seizures of incomplete penetrance: is STXBP1 not the only causative gene?
复制标题
DOI：
10.1186/s13039-015-0178-8
复制
发表时间：
2015
影响因子：
1.3
通讯作者：
Zink AM
中科院分区：
文献类型：
--
作者：
Ehret JK;Engels H;Cremer K;Becker J;Zimmermann JP;Wohlleber E;Grasshoff U;Rossier E;Bonin M;Mangold E;Bevot A;Schön S;Heilmann-Heimbach S;Dennert N;Mathieu-Dramard M;Lacaze E;Plessis G;de Broca A;Jedraszak G;Röthlisberger B;Miny P;Filges I;Dufke A;Andrieux J;Lee JA;Zink AM
到目前为止，大多数涉及染色体9q33.3-9q34.11亚带的微缺失都是通过对STXBP1的分析检测到的，STXBP1是一种已知会导致早期婴儿癫痫性脑病4和其他癫痫表型的基因。在一些无癫痫的智力残疾患者中也发现了STXBP1的功能丧失突变。因此，STXBP1被广泛认为是导致9q33.3-q34.11微缺失患者癫痫发作和智力残疾的基因。我们报告了5例染色体9q33.3-q34.11重叠微缺失的患者，其中4例以前未报道。他们的共同临床特征包括智力障碍、精神运动发育迟缓伴语言迟缓或缺失、肌肉张力低下和斜视。其中4例患者分别出现小头畸形和身材矮小。其中两名患者出现癫痫发作。从头缺失的范围从1.23到4.13 Mb，而患者3最小的缺失为432 kb，遗传自她的母亲，据报道她患有轻度智力残疾。9q33.3中这些缺失的最小重叠区（SRO）不包括STXBP1，但包括两个先前未与疾病相关的基因，RALGPS1和GARNL3。对至少156名轻度至重度特发性智力残疾患者的两个SRO基因RALGPS1和GARNL3进行测序，未发现任何致病突变。我们患者的基因表达分析显示，只有在相应基因缺失的患者中，GARNL3、RALGPS1和STXBP1的表达水平才会显著降低。因此，我们排除了STXBP1表达减少是本例缺失不包含STXBP1的患者癫痫发作的原因。我们认为，9q染色体上这一区域的微缺失会导致智力残疾、发育迟缓（尤其是言语、小头畸形、身材矮小、轻度畸形、斜视和不完全外显性癫痫）等临床症状，并可能构成一种新的连续基因缺失综合征，这种综合征不能完全用STXBP1的缺失来解释。本文的在线版本（doi:10.1186/s13039-015-0178-8）包含补充材料，仅供授权用户使用。
Most microdeletions involving chromosome sub-bands 9q33.3-9q34.11 to this point have been detected by analyses focused on STXBP1, a gene known to cause early infantile epileptic encephalopathy 4 and other seizure phenotypes. Loss-of-function mutations of STXBP1 have also been identified in some patients with intellectual disability without epilepsy. Consequently, STXBP1 is widely assumed to be the gene causing both seizures and intellectual disability in patients with 9q33.3-q34.11 microdeletions. We report five patients with overlapping microdeletions of chromosome 9q33.3-q34.11, four of them previously unreported. Their common clinical features include intellectual disability, psychomotor developmental delay with delayed or absent speech, muscular hypotonia, and strabismus. Microcephaly and short stature are each present in four of the patients. Two of the patients had seizures. De novo deletions range from 1.23 to 4.13 Mb, whereas the smallest deletion of 432 kb in patient 3 was inherited from her mother who is reported to have mild intellectual disability. The smallest region of overlap (SRO) of these deletions in 9q33.3 does not encompass STXBP1, but includes two genes that have not been previously associated with disease, RALGPS1 and GARNL3. Sequencing of the two SRO genes RALGPS1 and GARNL3 in at least 156 unrelated patients with mild to severe idiopathic intellectual disability detected no causative mutations. Gene expression analyses in our patients demonstrated significantly reduced expression levels of GARNL3, RALGPS1 and STXBP1 only in patients with deletions of the corresponding genes. Thus, reduced expression of STXBP1 was ruled out as a cause for seizures in our patient whose deletion did not encompass STXBP1. We suggest that microdeletions of this region on chromosome 9q cause a clinical spectrum including intellectual disability, developmental delay especially concerning speech, microcephaly, short stature, mild dysmorphisms, strabismus, and seizures of incomplete penetrance, and may constitute a new contiguous gene deletion syndrome which cannot completely be explained by deletion of STXBP1. The online version of this article (doi:10.1186/s13039-015-0178-8) contains supplementary material, which is available to authorized users.
影响因子：
--
作者：
Farhat N;Mamarbachi AM;Thorin E;Allen BG
通讯作者：
Allen BG