Aims: This quality analysis study was designed to review the indications, reports, and clinical consequences of 438 diagnostic next-generation sequencing (NGS) gene panel analyses for hereditary connective tissue disorders (HCTD). Methods: Molecular analyses were retrieved from laboratory databases and patient records, and compared to the clinical information in the requisition and classified according to the Human Phenotype Ontology. Results: In 123 of 438 NGS analyses, 156 sequence variants were reported in 33 of 54 genes analyzed. NGS analyses and, in some cases, postanalytic assessment resulted in identification of pathogenic variants in 40 (9%) of patients, and variants of uncertain significance were identified in 83 (19%) of cases analyzed. While cardiovascular abnormalities were the most common phenotype noted in the requisitions, no specific organ system could be identified in which the reported symptoms provided an actionable indication for the analysis. Certain health issues recorded in the patients' records were found to be frequently left out of requisitions. Conclusions: The interpretation of genetic sequence variants continues to be a significant challenge in HCTD. Although not associated with the highest diagnostic yield, cardiovascular disease and family history may be suitable indications for NGS due to the clinical consequences of the identification of a known or likely causative sequence variant for a vascular HCTD in patients and relatives.

中文翻译：

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通过遗传下一代测序诊断遗传性结缔组织疾病。

目的：这项质量分析研究旨在审查针对遗传性结缔组织疾病（HCTD）的438诊断性下一代测序（NGS）基因面板分析的适应症，报告和临床后果。方法：从实验室数据库和患者记录中检索分子分析，并将其与申请中的临床信息进行比较，并根据人类表型本体论进行分类。结果：在438个NGS分析中的123个中，在分析的54个基因中的33个中报告了156个序列变异。NGS分析以及在某些情况下进行分析后评估，可以确定40例患者（9％）的病原体变异，在83例（19％）的病例中鉴定出不确定性显着的变异。在申请书中，最常见的表型是心血管异常，无法确定特定的器官系统，其中报告的症状为分析提供了可行的指示。患者记录中记录的某些健康问题经常被排除在请购单之外。结论：遗传序列变异的解释仍然是HCTD中的重大挑战。尽管与最高诊断率无关，但由于鉴定患者和亲属中血管HCTD的已知或可能的致病性序列变异的临床后果，心血管疾病和家族史可能是NGS的合适适应症。发现记录经常被遗漏在请购单中。结论：遗传序列变异的解释仍然是HCTD的重大挑战。尽管与最高诊断率无关，但由于鉴定患者和亲属中血管HCTD的已知或可能的致病性序列变异的临床后果，心血管疾病和家族史可能是NGS的合适适应症。发现记录经常被遗漏在请购单中。结论：遗传序列变异的解释仍然是HCTD的重大挑战。尽管与最高诊断率无关，但由于鉴定患者和亲属中血管HCTD的已知或可能的致病性序列变异的临床后果，心血管疾病和家族史可能是NGS的合适适应症。