Hoischen Alexander, Landwehr Christina, Kabisch Sarah, Ding Xiao-Qi, Trost Detlef, Stropahl Gerhard, Wigger Marianne, Radlwimmer Bernhard, Weber Ruthild G, Haffner Dieter
Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
Pediatr Nephrol. 2009 Sep;24(9):1673-81. doi: 10.1007/s00467-009-1184-z. Epub 2009 May 15.
To investigate whether submicroscopic chromosomal deletions or duplications can be causative of unclear syndromic nephropathies, we analyzed ten patients with congenital abnormalities of the kidney and urinary tract or glomerulopathies combined with important extrarenal anomalies by whole-genome array-based comparative genomic hybridization. In a 14-year-old girl presenting with hematuria, proteinuria, mental retardation (MR), sensorineural hearing loss, dysmorphisms, and epilepsy, we detected a microdeletion in chromosome Xq22.3-q23. This deletion was verified and characterized by fluorescence in situ hybridization and multiplex ligation-dependent probe amplification analyses, found to be de novo, uniallelic and 3.3 Mb in size. Electron microscopy of a kidney biopsy showed glomerular basement membrane thinning and segmental splitting of the lamina densa compatible with Alport syndrome. Cranial magnetic resonance and diffusion tensor imaging detected a severe neuronal migration disorder with double cortex formation and pronounced reduction of the fronto-occipital tract system. Thus, in one of ten patients with unclear syndromic nephropathies we identified a previously undescribed contiguous gene syndrome at Xq22.3-q23. The microdeletion contains the X-linked Alport syndrome gene COL4A5, the MR genes FACL4 and PAK3, and parts of the X-chromosomal lissencephaly gene DCX associated with double cortex formation in girls, MR, and epilepsy. The phenotype in our patient combines features of the Alport-MR contiguous gene syndrome with lissencephaly.
为了研究亚微观染色体缺失或重复是否可能是不明原因的综合征性肾病的病因，我们通过基于全基因组阵列的比较基因组杂交技术，分析了10例患有先天性肾脏和尿路异常或肾小球病并伴有重要肾外异常的患者。在一名患有血尿、蛋白尿、智力发育迟缓、感音神经性听力损失、畸形和癫痫的14岁女孩中，我们在Xq22.3-q23染色体上检测到一个微缺失。通过荧光原位杂交和多重连接依赖探针扩增分析对该缺失进行了验证和特征分析，发现其为新发、单等位基因，大小为3.3 Mb。肾活检的电子显微镜检查显示肾小球基底膜变薄和致密层节段性分裂，符合Alport综合征。头颅磁共振成像和扩散张量成像检测到严重的神经元迁移障碍，伴有双皮质形成和额枕束系统明显减少。因此，在10例不明原因的综合征性肾病患者中，我们在Xq22.3-q23发现了一种先前未描述的相邻基因综合征。该微缺失包含X连锁的Alport综合征基因COL4A5、智力发育迟缓相关基因FACL4和PAK3，以及与女孩双皮质形成、智力发育迟缓及癫痫相关的X染色体无脑回畸形基因DCX的部分区域。我们患者的表型结合了Alport-智力发育迟缓相邻基因综合征和无脑回畸形的特征。
