■下一代测序(NGS)和生物信息学工具的快速发展使医生能够更快地获得基因检测结果,成本效益高,比以往任何时候都全面。大约50%的小儿感音神经性听力损失(SNHL)病例是由于遗传病因。因此,医师定期利用靶向测序小组来鉴定与SNHL相关的基因中的变异.这些小组允许早期检测致病变异,这允许医生为家庭提供预期的指导。由于存在不同分类的多基因变异,分子检测并不总是能揭示明确的病因。包括不确定重要性变体(VUS)的存在。这项研究旨在在存在其他多基因变异的情况下,对患有与II型Usher综合征相关的变异的患者进行初步的生物信息学表征。我们还为与医学遗传学家一起审查分子结果的医生提供了一种解释算法。
■对多基因和/或VUS结果记录的审查确定了几个潜在的感兴趣的受试者。出于本研究的目的,两个ADGRV1复合杂合子符合纳入标准.测序,数据处理,和变体调用(从序列数据鉴定变体的过程)在Invitae(旧金山CA)进行。初步分析遵循了美国医学遗传学和分子病理学协会(ACMG-AMP)在2015年和2019年提出的建议。本研究利用计算分析,预测数据,和人口数据以及来自图表审查的临床信息和ClinVar数据库中的公开信息。
■两个受试者被鉴定为基因ADGRV1中的变体的复合杂合子。受试者1的变异被预测为有害的,而受试者2的变体被预测为无害的。这些结果是基于ClinVar的变体的已知信息,多行计算数据,人口数据库,以及临床表现。
■通过NGS进行早期分子诊断是理想的,因为家庭能够获得广泛的资源,这些资源将最终支持孩子的病情发展。我们建议医生与医学遗传学家建立牢固的关系,并在向家庭提出建议之前仔细审查他们的解释,特别是在处理VUS时。VUS的重新分类工作得到了像我们这样的研究的支持,这些研究提供了变异的致病或良性影响的证据。
UNASSIGNED: Rapid advancements in Next Generation Sequencing (NGS) and bioinformatics tools have allowed physicians to obtain genetic testing results in a more rapid, cost-effective, and comprehensive manner than ever before. Around 50% of pediatric sensorineural hearing loss (SNHL) cases are due to a genetic etiology, thus physicians regularly utilize targeted sequencing panels that identify variants in genes related to SNHL. These panels allow for early detection of pathogenic variants which allows physicians to provide anticipatory guidance to families. Molecular testing does not always reveal a clear etiology due to the presence of multigenic variants with varying classifications, including the presence of Variants of Uncertain Significance (VUS). This study aims to perform a preliminary bioinformatics characterization of patients with variants associated with Type II Usher Syndrome in the presence of other multigenic variants. We also provide an interpretation algorithm for physicians reviewing molecular results with medical geneticists.
UNASSIGNED: Review of records for multigenic and/or VUS results identified several potential subjects of interest. For the purposes of this study, two ADGRV1 compound heterozygotes met inclusion criteria. Sequencing, data processing, and variant calling (the process by which variants are identified from sequence data) was performed at Invitae (San Francisco CA). The preliminary analysis followed the recommendations outlined by the American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) in 2015 and 2019. The present study utilizes computational analysis, predictive data, and population data as well as clinical information from chart review and publicly available information in the ClinVar database.
UNASSIGNED: Two subjects were identified as compound heterozygotes for variants in the gene ADGRV1. Subject 1\'s variants were predicted as deleterious, while Subject 2\'s variants were predicted as non-deleterious. These results were based on known information of the variants from ClinVar, multiple lines of computational data, population databases, as well as the clinical presentation.
UNASSIGNED: Early molecular diagnosis through NGS is ideal, as families are then able to access a wide range of resources that will ultimately support the child as their condition progresses. We recommend that physicians build strong relationships with medical geneticists and carefully review their interpretation before making recommendations to families, particularly when addressing the VUS. Reclassification efforts of VUS are supported by studies like ours that provide evidence of pathogenic or benign effects of variants.