Novel Comprehensive Diagnostic Strategy in Pitt-Hopkins Syndrome: Clinical Score and Further Delineation of the TCF4 Mutational Spectrum
Novel Comprehensive Diagnostic Strategy in Pitt-Hopkins Syndrome: Clinical Score and Further Delineation of the TCF4 Mutational Spectrum
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DOI：
10.1002/humu.21639
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发表时间：
2012-01-01
期刊：
影响因子：
3.9
通讯作者：
Giurgea, Irina
中科院分区：
文献类型：
--
作者：
Whalen, Sandra;Heron, Delphine;Giurgea, Irina
皮特-霍普金斯综合征（PTHS）以严重智力障碍和典型的面部完型为特征，是雷特样综合征临床谱的一部分。 TCF4编码碱性螺旋-环-螺旋（bHLH）转录因子，被鉴定为具有从头分子缺陷的致病基因。虽然 PTHS 似乎是一个可识别的临床实体，但它似乎仍然未被充分诊断，特别是当面部完型不太典型时。为了促进 PTHS 的诊断并提高其诊断率和特异性，我们调查了 33 名新患者并定义了临床诊断评分。对 112 名个体（79 名先前报告的患者和 33 名新患者）的分析使我们能够描绘出 TCF4 突变谱，其中 40% 为点突变，30% 为小缺失/插入，以及 30% 为缺失。其中大多数是私人突变并产生过早的终止密码子。错义突变位于 bHLH 结构域，这是一个突变热点。在携带截短、错义突变或缺失的患者之间没有观察到明显差异，进一步支持 TCF4 单倍体不足作为 PTHS 的分子机制。在本研究中，我们总结了TCF4分子病理学的现有知识，报告了TCF4数据库（http://www.LOVD.nl/TCF4）中的所有突变，并提出了一种新颖且全面的PTHS诊断策略。 Hum Mutat 33:64-72, 2012。(C) 2011 Wiley periodicals, Inc.
Pitt-Hopkins syndrome (PTHS), characterized by severe intellectual disability and typical facial gestalt, is part of the clinical spectrum of Rett-like syndromes. TCF4, encoding a basic helix-loop-helix (bHLH) transcription factor, was identified as the disease-causing gene with de novo molecular defects. While PTHS appears to be a recognizable clinical entity, it seems to remain underdiagnosed, especially when facial gestalt is less typical. With the aim to facilitate the diagnosis of PTHS and to increase its rate and specificity, we have investigated 33 novel patients and defined a Clinical Diagnosis Score. Analysis of 112 individuals (79 previously reported and 33 novel patients) allowed us to delineate the TCF4 mutational spectrum, with 40% point mutations, 30% small deletions/insertions, and 30% deletions. Most of these were private mutations and generated premature stop codons. Missense mutations were localized in the bHLH domain, which is a mutational hotspot. No obvious difference was observed between patients harboring truncating, missense mutations, or deletions, further supporting TCF4 haploinsufficiency as the molecular mechanism underlying PTHS. In this study, we have summarized the current knowledge of TCF4 molecular pathology, reported all the mutations in the TCF4 database (http://www.LOVD.nl/TCF4), and present a novel and comprehensive diagnostic strategy for PTHS. Hum Mutat 33:64-72, 2012. (C) 2011 Wiley Periodicals, Inc.