Success and Pitfalls of Genetic Testing in Undiagnosed Diseases: Whole Exome Sequencing and Beyond.
Success and Pitfalls of Genetic Testing in Undiagnosed Diseases: Whole Exome Sequencing and Beyond.
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DOI：
10.3390/genes14061241
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发表时间：
2023-06-10
期刊：
影响因子：
3.5
通讯作者：
Percesepe, Antonio
中科院分区：
文献类型：
--
作者：
Barili, Valeria;Ambrosini, Enrico;Uliana, Vera;Bellini, Melissa;Vitetta, Giulia;Martorana, Davide;Cannizzaro, Ilenia Rita;Taiani, Antonietta;De Sensi, Erika;Caggiati, Patrizia;Hilton, Sarah;Banka, Siddharth;Percesepe, Antonio
关键词：
迫切需要新的方法来揭示神经发育障碍(NDD)的分子病因学。即使使用强大的工具，如整个外显子组测序(WES)，诊断过程仍然可能被证明是漫长和艰巨的，因为这些疾病具有高度的临床和遗传异质性。提高诊断率的主要策略是基于家系隔离，通过反向表型重新评估临床特征，重新分析未解决的基于NGS的病例和表观遗传学功能研究。在本文中，我们描述了从应用Trio WES的NDD患者队列中选择的三例病例，以强调在诊断过程中遇到的典型挑战：(1)由MEIS2的错义变体引起的极其罕见的疾病，通过更新的Solve-RD重新分析确定；(2)1例具有Noonan样特征的患者，其中NGS分析揭示了NIPBL中的一种新的变异导致Cornelia de Lange综合征；以及(3)1例涉及染色质重塑复合体的基因的从头变异，对其表观遗传学特征的研究排除了致病作用。在这方面，我们的目标是(1)提供一个例子，说明通过罕见疾病网络项目对所有未解决的病例进行遗传重新分析的相关性；(2)指出反向表型在解释遗传结果中的作用和不确定性；以及(3)描述神经发育综合征中甲基化标记用于验证不确定意义的变异。
Novel approaches to uncover the molecular etiology of neurodevelopmental disorders (NDD) are highly needed. Even using a powerful tool such as whole exome sequencing (WES), the diagnostic process may still prove long and arduous due to the high clinical and genetic heterogeneity of these conditions. The main strategies to improve the diagnostic rate are based on family segregation, re-evaluation of the clinical features by reverse-phenotyping, re-analysis of unsolved NGS-based cases and epigenetic functional studies. In this article, we described three selected cases from a cohort of patients with NDD in which trio WES was applied, in order to underline the typical challenges encountered during the diagnostic process: (1) an ultra-rare condition caused by a missense variant in MEIS2, identified through the updated Solve-RD re-analysis; (2) a patient with Noonan-like features in which the NGS analysis revealed a novel variant in NIPBL causing Cornelia de Lange syndrome; and (3) a case with de novo variants in genes involved in the chromatin-remodeling complex, for which the study of the epigenetic signature excluded a pathogenic role. In this perspective, we aimed to (i) provide an example of the relevance of the genetic re-analysis of all unsolved cases through network projects on rare diseases; (ii) point out the role and the uncertainties of the reverse phenotyping in the interpretation of the genetic results; and (iii) describe the use of methylation signatures in neurodevelopmental syndromes for the validation of the variants of uncertain significance.
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影响因子：
16.6
作者：
Garcia P;Fernandez-Hernandez R;Cuadrado A;Coca I;Gomez A;Maqueda M;Latorre-Pellicer A;Puisac B;Ramos FJ;Sandoval J;Esteller M;Mosquera JL;Rodriguez J;Pié J;Losada A;Queralt E
通讯作者：
Queralt E
癫痫合并智力障碍/精神发育迟滞患者全外显子组测序数据的再分析
影响因子：
3.5
作者：
Li, Jinliang;Gao, Kai;Jiang, Yuwu
通讯作者：
Jiang, Yuwu
DOI：
10.1108/amhid-10-2015-0050
发表时间：
2016-01-01
影响因子：
1.1
作者：
Bertelli, Marco O.;Munir, Kerim;Salvador-Carulla, Luis
通讯作者：
Salvador-Carulla, Luis
影响因子：
--
作者：
Levy MA;McConkey H;Kerkhof J;Barat-Houari M;Bargiacchi S;Biamino E;Bralo MP;Cappuccio G;Ciolfi A;Clarke A;DuPont BR;Elting MW;Faivre L;Fee T;Fletcher RS;Cherik F;Foroutan A;Friez MJ;Gervasini C;Haghshenas S;Hilton BA;Jenkins Z;Kaur S;Lewis S;Louie RJ;Maitz S;Milani D;Morgan AT;Oegema R;Østergaard E;Pallares NR;Piccione M;Pizzi S;Plomp AS;Poulton C;Reilly J;Relator R;Rius R;Robertson S;Rooney K;Rousseau J;Santen GWE;Santos-Simarro F;Schijns J;Squeo GM;St John M;Thauvin-Robinet C;Traficante G;van der Sluijs PJ;Vergano SA;Vos N;Walden KK;Azmanov D;Balci T;Banka S;Gecz J;Henneman P;Lee JA;Mannens MMAM;Roscioli T;Siu V;Amor DJ;Baynam G;Bend EG;Boycott K;Brunetti-Pierri N;Campeau PM;Christodoulou J;Dyment D;Esber N;Fahrner JA;Fleming MD;Genevieve D;Kerrnohan KD;McNeill A;Menke LA;Merla G;Prontera P;Rockman-Greenberg C;Schwartz C;Skinner SA;Stevenson RE;Vitobello A;Tartaglia M;Alders M;Tedder ML;Sadikovic B
通讯作者：
Sadikovic B
影响因子：
9.8
作者：
Choufani, Sanaa;Gibson, William T.;Weksberg, Rosanna
通讯作者：
Weksberg, Rosanna