Vona Barbara, Maroofian Reza, Mendiratta Geetu, Croken Matthew, Peng Siwu, Ye Xiaoqian, Rezazadeh Jamileh, Bahena Paulina, Lekszas Caroline, Haaf Thomas, Edelmann Lisa, Shi Lisong
Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany.
Medical Research, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK.
Mol Syndromol. 2017 Dec;9(1):5-14. doi: 10.1159/000480458. Epub 2017 Sep 22.
Multilocus analysis of rare or genetically heterogeneous diseases is a distinct advantage of next-generation sequencing (NGS) over conventional single-gene investigations. Recent studies have begun to uncover an under-recognized prevalence of dual molecular diagnoses in patients with a "blended" phenotype that is the result of 2 clinical diagnoses involving 2 separate genetic loci. This blended phenotype could be mistakenly interpreted as a novel clinical extension of a single-gene disorder. In this study, we ascertained a proband from a large consanguineous Iranian family who manifests postlingual, progressive, moderate hearing loss in addition to suspected Ellis-van Creveld syndrome phenotype. NGS with a customized skeletal dysplasia panel containing over 370 genes and subsequent bioinformatics analysis disclosed 2 homozygous mutations in (c.2653C>T; p.Arg885*) and (c.966dup; p.Thr323His*19), respectively. This study highlights a dual molecular diagnosis in a patient with a blending of 2 distinct phenotypes and illustrates the advantage and importance of this staple technology to facilitate rapid and comprehensive genetic dissection of a heterogeneous phenotype. The differentiation between phenotypic expansion of a genetic disorder and a blended phenotype that is due to more than one distinct genetic aberration is essential in order to reduce the diagnostic odyssey endured by patients.
对于罕见病或基因异质性疾病进行多位点分析，是新一代测序（NGS）相较于传统单基因研究的一项显著优势。最近的研究已开始揭示，在具有“混合”表型的患者中，双分子诊断的患病率未得到充分认识，这种“混合”表型是由涉及两个独立基因座的两种临床诊断导致的。这种混合表型可能会被错误地解释为单基因疾病的一种新的临床延伸。在本研究中，我们从一个伊朗近亲大家族中确定了一名先证者，该先证者除疑似患有埃利斯-范克里弗德综合征表型外，还表现出迟发性、进行性、中度听力损失。使用包含370多个基因的定制骨骼发育异常检测板进行NGS及后续生物信息学分析，分别在 （c.2653C>T；p.Arg885*）和 （c.966dup；p.Thr323His*19）中发现了两个纯合突变。本研究突出了一名具有两种不同表型混合特征患者的双分子诊断，并说明了这项主要技术在促进对异质性表型进行快速全面基因剖析方面的优势和重要性。区分遗传病的表型扩展与由多种不同基因畸变导致的混合表型至关重要，以便减少患者所经历的诊断历程。
