NGS and phenotypic ontology-based approaches increase the diagnostic yield in syndromic retinal diseases.
NGS and phenotypic ontology-based approaches increase the diagnostic yield in syndromic retinal diseases.
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DOI：
10.1007/s00439-021-02343-7
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发表时间：
2021-12
期刊：
影响因子：
5.3
通讯作者：
Ayuso C
中科院分区：
文献类型：
--
作者：
Perea-Romero I;Blanco-Kelly F;Sanchez-Navarro I;Lorda-Sanchez I;Tahsin-Swafiri S;Avila-Fernandez A;Martin-Merida I;Trujillo-Tiebas MJ;Lopez-Rodriguez R;Rodriguez de Alba M;Iancu IF;Romero R;Quinodoz M;Hakonarson H;Garcia-Sandova B;Minguez P;Corton M;Rivolta C;Ayuso C
综合征性视网膜疾病（SRD）是一组复杂的遗传性系统性疾病，具有挑战性的分子基础和临床管理。我们的主要目标是通过应用结构化表型本体和基于下一代测序（NGS）的管道来改善临床和分子SRD诊断。对100名先证者进行了前瞻性和回顾性队列研究，这些先证者事先诊断为非Usher SRD，使用现有的临床数据，包括人类表型本体论注释，并进一步分类为7个临床类别（纤毛病变，特定综合征和其他5个）。根据可用性，使用不同的分子和生物信息学方法评估回顾性分子诊断。随后，使用其他NGS方法前瞻性筛选未表征的先证者，以扩大分析基因的数量。表型分类后，纤毛病变是最常见的SRD（35%）。获得了52%的全球表征率，6例不完全表征的基因，部分解释了表型。在前瞻性病例（83%）和可识别综合征（62%）亚组中，表征率得到提高。在确定致病基因后，27%的完全特征化病例被重新分类为不同的临床类别。临床外显子组测序是前瞻性病例最合适的第一层方法，而全外显子组测序和生物信息学再分析将未表征的回顾性病例的诊断增加到45%，大多数是那些具有非特异性症状的病例。我们的研究描述了在日常临床实践中对SRD的综合方法，以及彻底的临床评估和选择最合适的分子检测用于解决这些复杂病例和阐明新关联的重要性。在线版本包含补充材料，可通过10.1007/s 00439 -021-02343-7获得。
Syndromic retinal diseases (SRDs) are a group of complex inherited systemic disorders, with challenging molecular underpinnings and clinical management. Our main goal is to improve clinical and molecular SRDs diagnosis, by applying a structured phenotypic ontology and next-generation sequencing (NGS)-based pipelines. A prospective and retrospective cohort study was performed on 100 probands with an a priori diagnosis of non-Usher SRDs, using available clinical data, including Human Phenotype Ontology annotation, and further classification into seven clinical categories (ciliopathies, specific syndromes and five others). Retrospective molecular diagnosis was assessed using different molecular and bioinformatic methods depending on availability. Subsequently, uncharacterized probands were prospectively screened using other NGS approaches to extend the number of analyzed genes. After phenotypic classification, ciliopathies were the most common SRD (35%). A global characterization rate of 52% was obtained, with six cases incompletely characterized for a gene that partially explained the phenotype. An improved characterization rate was achieved addressing prospective cases (83%) and well-recognizable syndrome (62%) subgroups. The 27% of the fully characterized cases were reclassified into a different clinical category after identification of the disease-causing gene. Clinical-exome sequencing is the most appropriate first-tier approach for prospective cases, whereas whole-exome sequencing and bioinformatic reanalysis increases the diagnosis of uncharacterized retrospective cases to 45%, mostly those with unspecific symptoms. Our study describes a comprehensive approach to SRDs in daily clinical practice and the importance of thorough clinical assessment and selection of the most appropriate molecular test to be used to solve these complex cases and elucidate novel associations. The online version contains supplementary material available at 10.1007/s00439-021-02343-7.
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影响因子：
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DOI：
10.1073/pnas.1913179117
发表时间：
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影响因子：
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