Four patients with speech delay, seizures and variable corpus callosum thickness sharing a 0.440 Mb deletion in region 1q44 containing the HNRPU gene
Four patients with speech delay, seizures and variable corpus callosum thickness sharing a 0.440 Mb deletion in region 1q44 containing the HNRPU gene
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DOI：
10.1016/j.ejmg.2010.04.001
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发表时间：
2010-07-01
影响因子：
1.9
通讯作者：
Poot, Martin
中科院分区：
文献类型：
--
作者：
Caliebe, Almuth;Kroes, Hester Y.;Poot, Martin
结构基因组畸变经常与高度可变的先天性表型相关，包括智力低下和发育迟缓。虽然这些畸变中的一些可能导致可识别的表型，但高度的表型变异性通常使全面的临床和遗传诊断复杂化。我们描述了4例染色体区域1q44重叠缺失的患者，他们表现出发育迟缓，特别是表达性语音，癫痫发作，肌张力减退，中枢神经系统异常，包括其中3例胼胝体异常的可变厚度。高分辨率寡核苷酸和SNP阵列为基础的节段性非整倍性分析表明，这三名患者共享一个0.440 Mb的间质缺失，这并不重叠与先前公布的1q44缺失的共识区域。两个拷贝的AKT3和ZNF 238，两个先前提出的剂量敏感的候选基因的小头畸形和胼胝体发育不全，保留在我们的两个病人。我们的患者共有的缺失包括FAM36A、HNRPU、EFCAB2和KIF26B基因。由于HNRPU参与胚胎脑发育的调节，这代表了一种新的可能的候选基因，用于1q44缺失患者的发育延迟、言语延迟、张力减退、胼胝体发育不良或发育不全以及癫痫发作的组合。由于只有一个的两个病人包括ZNF 124基因缺失显示蚓部发育不全，仅仅半合子该基因是不足以导致这种异常。此外，为了调和胼胝体厚度的变化，需要考虑其他机制，如半合子突变的暴露、位置效应和与其他基因座的可能相互作用。(C)2010年Elsevier Masson SAS。All rights reserved.
Structural genome aberrations are frequently associated with highly variable congenital phenotypes involving mental retardation and developmental delay. Although some of these aberrations may result in recognizable phenotypes, a high degree of phenotypic variability often complicates a comprehensive clinical and genetic diagnosis. We describe four patients with overlapping deletions in chromosomal region 1q44, who show developmental delay, in particular of expressive speech, seizures, hypotonia, CNS anomalies, including variable thickness of the abnormal corpus callosum in three of them. High resolution oligonucleotide and SNP array-based segmental aneuploidy profiling showed that these three patients share a 0.440 Mb interstitial deletion, which does not overlap with previously published consensus regions of 1q44 deletions. Two copies of AKT3 and ZNF238, two previously proposed dosage sensitive candidate genes for microcephaly and agenesis of the corpus callosum, were retained in two of our patients. The deletion shared by our patients encompassed the FAM36A, HNRPU, EFCAB2 and KIF26B genes. Since HNRPU is involved in the regulation of embryonic brain development, this represents a novel plausible candidate gene for the combination of developmental delay, speech delay, hypotonia, hypo-or agenesis of the corpus callosum, and seizures in patients with 1q44 deletions. Since only one of the two patients with deletions including the ZNF124 gene showed a vermis hypoplasia, mere hemizygosity for this gene is not sufficient to cause this anomaly. Moreover, to reconcile the variability in the corpus callosum thickness, additional mechanisms, such as unmasking of hemizygous mutations, position effects and possible interactions with other loci need consideration. (C) 2010 Elsevier Masson SAS. All rights reserved.