Recurrent reciprocal genomic Rearrangements of 17q12 are associated with renal disease, diabetes, and epilepsy
Recurrent reciprocal genomic Rearrangements of 17q12 are associated with renal disease, diabetes, and epilepsy
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DOI：
10.1086/522591
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发表时间：
2007-11-01
影响因子：
9.8
通讯作者：
Bellanne-Chantelot, Christine
中科院分区：
文献类型：
--
作者：
Mefford, Heather C.;Clauin, Severine;Bellanne-Chantelot, Christine
大多数关于基因组疾病的研究都集中在有认知障碍和/或周围神经系统缺陷的患者身上。为了拓宽这种疾病模型的表型谱，我们通过基于阵列的比较基因组杂交，评估了155个来自胎儿的尸检样本，这些胎儿在易于反复重排的区域具有明确的发育病理。我们发现，6%的胎儿材料显示出微缺失或微复制的证据，其中包括三个独立的事件，可能是由节段复制之间的不等交换引起的。在一个患有多囊肾发育不良的胎儿身上发现的其中一个微缺失，包括17q12上的TCF2基因，以前在成熟期糖尿病和儿童肾脏异常的子集中被证明是突变的。对不同患者队列中断裂点的精细绘制图显示，从先天性肾脏异常到年轻的5型成熟型糖尿病的表型，个体中反复出现1.5-Mb从头开始缺失。我们还发现了这种相互重复，似乎在癫痫患者的样本中丰富。我们描述了与糖尿病相关的复发性基因组疾病的第一个例子。
Most studies of genomic disorders have focused on patients with cognitive disability and/or peripheral nervous system defects. In an effort to broaden the phenotypic spectrum of this disease model, we assessed 155 autopsy samples from fetuses with well-defined developmental pathologies in regions predisposed to recurrent rearrangement, by array-based comparative genomic hybridization. We found that 6% of fetal material showed evidence of microdeletion or microduplication, including three independent events that likely resulted from unequal crossing-over between segmental duplications. One of the microdeletions, identified in a fetus with multicystic dysplastic kidneys, encompasses the TCF2 gene on 17q12, previously shown to be mutated in maturity-onset diabetes, as well as in a subset of pediatric renal abnormalities. Fine-scale mapping of the breakpoints in different patient cohorts revealed a recurrent 1.5-Mb de novo deletion in individuals with phenotypes that ranged from congenital renal abnormalities to maturity-onset diabetes of the young type 5. We also identified the reciprocal duplication, which appears to be enriched in samples from patients with epilepsy. We describe the first example of a recurrent genomic disorder associated with diabetes.