Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing An Interim Report of the Genomic Medicine for III Neonates and Infants (GEMINI) Study
Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing An Interim Report of the Genomic Medicine for III Neonates and Infants (GEMINI) Study
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DOI：
10.1001/jamapediatrics.2020.5906
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发表时间：
2021-02-15
期刊：
影响因子：
26.1
通讯作者：
Davis, Jonathan M.
中科院分区：
文献类型：
--
作者：
Maron, Jill L.;Kingsmore, Stephen F.;Davis, Jonathan M.
重要性一个靶向基因组测序平台集中在疾病提出的第一年的生活可能会减少财政和伦理挑战与快速全基因组sequencing.Objective报告中期变异和相关的解释正在进行的研究比较快速全基因组测序与一个新的靶向基因组平台组成的1722个可操作的基因靶向疾病提出在婴儿期。和参与者基因组医学在生病的新生儿和婴儿（GEMINI）研究是一个前瞻性的，多中心的临床试验，预计招募400例患者。该研究在美国6家医院进行。年龄小于1岁的疑似患有遗传性疾病的住院婴儿符合资格。本文报告了前113例入组患者的结果。患者招募于2019年7月开始，入组患者的中期分析于2020年3月至6月进行。干预患者（先证者）和父母（三人组，如可用）在两个基因组平台上同时进行检测。每个实验室进行其自身的表型驱动的解释，并对其他结果设盲。主要结果和测量根据美国医学遗传学和基因组学学会致病性（P）、可能致病性（LP）或未知意义的变异（VUS）标准对变异进行分类。结果113例患者孕龄23 ~ 40周，经后27 ~ 83周。67例患者（59%）为男性。51名患者（45%）返回了诊断和/或VUS，而62名（55%）的结果为阴性。83例患者（73%）的平台间结果一致。发现37例患者（33%）在2个或2个平台上存在P/LP变异，14例（12%）存在可能与表型相关的VUS。诊断时的中位生命天数为22天（范围。3-313天）。29名患有P/LP变异的婴儿（78%）的临床护理发生了显着变化。在7例三重奏中报告了偶然发现。51例阳性病例。34（67%）不同的报告结果，因为有针对性的平台，变异的解释，过滤的差异，或多个causes.CONCLUSIONS和相关性的技术限制全面的基因检测变得更加常规，这些数据突出了至关重要的变异检测能力的现有基因组测序技术和显着的局限性，必须更好地理解。
IMPORTANCE A targeted genomic sequencing platform focused on diseases presenting in the first year of life may minimize financial and ethical challenges associated with rapid whole-genomic sequencing.OBJECTIVE To report interim variants and associated interpretations of an ongoing study comparing rapid whole-genomic sequencing with a novel targeted genomic platform composed of 1722 actionable genes targeting disorders presenting in infancy.DESIGN, SETTING, AND PARTICIPANTS The Genomic Medicine in Ill Neonates and Infants (GEMINI) study is a prospective, multicenter clinical trial with projected enrollment of 400 patients. The study is being conducted at 6 US hospitals. Hospitalized infants younger than 1 year of age suspected of having a genetic disorder are eligible. Results of the first 113 patients enrolled are reported here. Patient recruitment began in July 2019, and the interim analysis of enrolled patients occurred from March to June 2020.INTERVENTIONS Patient (proband) and parents (trios, when available) were tested simultaneously on both genomic platforms. Each laboratory performed its own phenotypically driven interpretation and was blinded to other results.MAIN OUTCOMES AND MEASURES Variants were classified according to the American College of Medical Genetics and Genomics standards of pathogenic (P), likely pathogenic (LP), or variants of unknown significance (VUS). Chromosomal and structural variations were reported by rapid whole-genomic sequencing.RESULTS Gestational age of 113 patients ranged from 23 to 40 weeks and postmenstrual age from 27 to 83 weeks. Sixty-seven patients (59%) were male. Diagnostic and/or VUS were returned for 51 patients (45%), while 62 (55%) had negative results. Results were concordant between platforms in 83 patients (73%). Thirty-seven patients (33%) were found to have a P/LP variant by 2 or both platforms and 14 (12%) had a VUS possibly related to phenotype. The median day of life at diagnosis was 22 days (range. 3-313 days). Significant alterations in clinical care occurred in 29 infants (78%) with a P/LP variant. Incidental findings were reported in 7 trios. Of 51 positive cases. 34 (67%) differed in the reported result because of technical limitations of the targeted platform, interpretation of the variant, filtering discrepancies, or multiple causes.CONCLUSIONS AND RELEVANCE As comprehensive genetic testing becomes more routine, these data highlight the critically important variant detection capabilities of existing genomic sequencing technologies and the significant limitations that must be better understood.