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与TBL1XR1基因中p.Tyr446Cys错义突变相关的皮尔庞特综合征。

Pierpont syndrome associated with the p.Tyr446Cys missense mutation in TBL1XR1.

作者信息

Slavotinek Anne, Pua Heather, Hodoglugil Ugur, Abadie Jude, Shieh Joseph, Van Ziffle Jessica, Kvale Mark, Lee Hane, Kwok Pui-Yan, Risch Neil, Sabbadini Marta

机构信息

Division of Medical Genetics, Department of Pediatrics, UCSF, San Francisco, CA 94143-2711, USA.

Dept. of Pathology, UCSF, 513 Parnassus Ave, San Francisco, CA 94143, USA.

出版信息

Eur J Med Genet. 2017 Oct;60(10):504-508. doi: 10.1016/j.ejmg.2017.07.003. Epub 2017 Jul 4.

Abstract

We present a 7-year old male with severe delays, hypotonia and dysmorphic features who had striking, deep palmar and plantar creases and pillowing of the soft tissues of the palms and soles. His facial features included a high anterior hairline, small eyes with narrowed palpebral fissures, a bulbous nasal tip with a short columella, and a large mouth with a thin upper vermilion, and small chin. He had a submucous cleft palate, bilateral cryptorchidism and hydronephrosis. Cranial imaging demonstrated an Arnold Chiari malformation that was also present in his maternal uncle by report. Exome sequencing revealed a de novo heterozygous sequence variant, p.Tyr446Cys, in TBL1XR1 that has previously been reported in six patients with Pierpont syndrome. This sequence variant occurs in the carboxy-terminal, WD40 domain of the protein. As TBL1XR1 is a critical component of the NCoR/SMRT co-repressor complex and the WD40 repeats are hypothesized to interact with histone H2B and H4, the mutation may impact protein interactions necessary for stabilizing the complex with chromatin. De novo missense and frameshift mutations and deletions involving TBL1XR1 have been described in patients with intellectual disability and autism, but without any of the dysmorphic findings or malformations associated with Pierpont syndrome, implying a mutation-specific mechanism for the pathogenicity of p.Tyr446Cys. Our case is the first individual with this mutation to have a submucous cleft palate and hydronephrosis, although his severe delays, hypotonia, dysmorphic findings and emerging scoliosis appear consistent with previous reports. His distinctive facial and digital features are further evidence that p.Tyr446Cys results in a clinically recognizable, syndromic form of intellectual disability in contrast to other TBL1XR1 mutations.

摘要

我们报告一名7岁男性,有严重发育迟缓、肌张力减退和畸形特征,手掌和足底有明显的深褶痕以及手掌和足底软组织的肿胀。他的面部特征包括前额发际线高、睑裂狭窄的小眼睛、鼻尖球状且鼻小柱短、嘴巴大且上唇朱红色薄以及下巴小。他患有黏膜下腭裂、双侧隐睾和肾积水。头颅影像学检查显示存在阿诺德·奇亚里畸形,据报告其母系舅舅也有此畸形。外显子组测序揭示了TBL1XR1基因中的一个新生杂合序列变异,即p.Tyr446Cys,此前在6例皮尔庞特综合征患者中已有报道。这个序列变异发生在该蛋白的羧基末端WD40结构域。由于TBL1XR1是NCoR/SMRT共抑制复合物的关键组成部分,且推测WD40重复序列与组蛋白H2B和H4相互作用,该突变可能影响与染色质稳定复合物所需的蛋白质相互作用。在智力障碍和自闭症患者中已描述了涉及TBL1XR1的新生错义、移码突变和缺失,但没有与皮尔庞特综合征相关的任何畸形表现或畸形,这意味着p.Tyr446Cys致病性存在突变特异性机制。我们的病例是首例有此突变且患有黏膜下腭裂和肾积水的个体,尽管他的严重发育迟缓、肌张力减退、畸形表现和新发脊柱侧弯与先前报告一致。他独特的面部和手部特征进一步证明,与其他TBL1XR1突变相比,p.Tyr446Cys导致了一种临床上可识别的、综合征形式的智力障碍。

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