德国波恩大学Peter M. Krawitz团队发现将二代表型分型整合到针对罕见疾病患者的国家框架，可改善遗传诊断并产生新的分子发现。该研究于2024年7月22日在线发表于国际一流学术期刊《自然—遗传学》。

在TRANSLATE NAMSE，一项为期三年的前瞻性研究中，研究人员评估了基于德国多学科专业知识的新诊断概念。研究人员对1577名患者的表型和分子遗传数据进行了系统调查，这些患者接受了外显子组测序，并部分使用了下一代表型分析方法。32%的患者（总计370种不同的分子遗传原因）确立了分子遗传诊断，其中大多数疾病的患病率低于1:50000。

在诊断过程中，研究人员发现了34个新的和23个候选基因型-表型关联，主要是在患有神经发育障碍的个体中。通过GestaltMatcher对同意进行面部图像计算机辅助分析的子队列进行的测序数据优先级排序比单纯依靠临床特征和分子评分的方法更为有效。该研究表明，使用二代测序和表型分析在常规医疗中诊断罕见疾病，并通过多学科团队发现新病因的协同作用。

据悉，罕见病患者对医疗系统构成了结构性挑战，因为需要专业的临床知识来确立诊断。

附：英文原文

Title: Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings

Author: Schmidt, Axel, Danyel, Magdalena, Grundmann, Kathrin, Brunet, Theresa, Klinkhammer, Hannah, Hsieh, Tzung-Chien, Engels, Hartmut, Peters, Sophia, Knaus, Alexej, Moosa, Shahida, Averdunk, Luisa, Boschann, Felix, Sczakiel, Henrike Lisa, Schwartzmann, Sarina, Mensah, Martin Atta, Pantel, Jean Tori, Holtgrewe, Manuel, Bsch, Annemarie, Wei, Claudia, Weinhold, Natalie, Suter, Aude-Annick, Stoltenburg, Corinna, Neugebauer, Julia, Kallinich, Tillmann, Kaindl, Angela M., Holzhauer, Susanne, Bhrer, Christoph, Bufler, Philip, Kornak, Uwe, Ott, Claus-Eric, Schlke, Markus, Nguyen, Hoa Huu Phuc, Hoffjan, Sabine, Grasemann, Corinna, Rothoeft, Tobias, Brinkmann, Folke, Matar, Nora, Sivalingam, Sugirthan, Perne, Claudia, Mangold, Elisabeth, Kreiss, Martina, Cremer, Kirsten, Betz, Regina C., Mcke, Martin, Grigull, Lorenz, Klockgether, Thomas, Spier, Isabel, Heimbach, Andr, Bender, Tim, Brand, Fabian, Stieber, Christiane, Morawiec, Alexandra Marzena, Karakostas, Pantelis, Schfer, Valentin S., Bernsen, Sarah, Weydt, Patrick, Castro-Gomez, Sergio, Aziz, Ahmad, Grobe-Einsler, Marcus, Kimmich, Okka, Kobeleva, Xenia, nder, Demet, Lesmann, Hellen, Kumar, Sheetal, Tacik, Pawel, Basin, Meghna Ahuja, Incardona, Pietro, Lee-Kirsch, Min Ae, Berner, Reinhard, Schuetz, Catharina

Issue&Volume: 2024-07-22

Abstract: Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype–phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams.

DOI: 10.1038/s41588-024-01836-1

Source: https://www.nature.com/articles/s41588-024-01836-1