19q13.11 cryptic deletion: description of two new cases and indication for a role of WTIP haploinsufficiency in hypospadias.
19q13.11 cryptic deletion: description of two new cases and indication for a role of WTIP haploinsufficiency in hypospadias.
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DOI：
10.1038/ejhg.2012.19
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发表时间：
2012-08
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发育迟缓/智力障碍、言语障碍、出生前和出生后发育迟缓、小头畸形、外胚层发育不良迹象和男性生殖器畸形(尿道下裂)是最近出现的19q13.11缺失综合征的表型核心。使用阵列-CGH进行全基因组筛查，我们在两名患者中检测到染色体带19q13.11的间隙缺失，表现出可识别的畸形模式，如在这种亚显微基因组失衡的其他实例中所描述的那样。在我们的患者中检测到的缺失与以前报道的病例进行了比较，从而将这种微缺失综合征的最小重叠区域(MOR)细化到324 kb。该区域包含5个基因：属于KRAB-ZNF亚家族的4个锌指(ZNF)基因(ZNF302、ZNF181、ZNF599和ZNF30)和LOC400685。在我们的男性患者1和文献中另外6个男性病例的基础上，我们还强调了更大的19q13.11缺失，包括位于MOR近端的Wilms肿瘤相互作用蛋白(WTIP)基因，导致尿道下裂，使该基因由于其与WT1的众所周知的相互作用而成为这种生殖器异常的可能候选基因。虽然涉及19q13.11的KRAB-ZNF基因拷贝数改变的表型效应的机制尚未明确，但我们认为它们的单倍性不足是19q13.11缺失综合征表型核心的最有可能的候选因素。此外，我们假设WTIP基因单倍性不足是导致尿道下裂的原因。
Developmental delay/intellectual disabilities, speech disturbance, pre- and postnatal growth retardation, microcephaly, signs of ectodermal dysplasia, and genital malformations in males (hypospadias) represent the phenotypic core of the recent emerging 19q13.11 deletion syndrome. Using array-CGH for genome-wide screening we detected an interstitial deletion of chromosome band 19q13.11 in two patients exhibiting the recognizable pattern of malformations as described in other instances of this submicroscopic genomic imbalance. The deletion detected in our patients has been compared with previously reported cases leading to the refinement of the minimal overlapping region (MOR) for this microdeletion syndrome to 324 kb. This region encompasses five genes: four zinc finger (ZNF) genes belonging to the KRAB-ZNF subfamily (ZNF302, ZNF181, ZNF599, and ZNF30) and LOC400685. On the basis of our male patient 1 and on further six male cases of the literature, we also highlighted that larger 19q13.11 deletions including the Wilms tumor interacting protein (WTIP) gene, proximal to the MOR, results in hypospadias making this gene a possible candidate for this genital abnormality due to its well-known interaction with WT1. Although the mechanism underlying the phenotypic effects of copy number alterations involving KRAB-ZNF genes at 19q13.11 has not clearly been established, we suggest their haploinsufficiency as the most likely candidate for the phenotypic core of the 19q13.11 deletion syndrome. In addition, we hypothesized WTIP gene haploinsufficiency as responsible for hypospadias.
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