Genome Sequencing as a Diagnostic Test in Children With Unexplained Medical Complexity.
Genome Sequencing as a Diagnostic Test in Children With Unexplained Medical Complexity.
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DOI：
10.1001/jamanetworkopen.2020.18109
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发表时间：
2020-09-01
影响因子：
13.8
通讯作者：
Hayeems RZ
中科院分区：
文献类型：
--
作者：
Costain G;Walker S;Marano M;Veenma D;Snell M;Curtis M;Luca S;Buera J;Arje D;Reuter MS;Thiruvahindrapuram B;Trost B;Sung WWL;Yuen RKC;Chitayat D;Mendoza-Londono R;Stavropoulos DJ;Scherer SW;Marshall CR;Cohn RD;Cohen E;Orkin J;Meyn MS;Hayeems RZ
在患有无法解释的医学复杂性和先前基因检测结果为阴性的儿童中，基因组测序的诊断率是多少？在这项包括来自49个家庭的138名个体的队列研究中，基因组测序检测到了之前通过传统基因检测发现的所有基因组变异，并为31%的患者做出了新的诊断。这项研究表明，由于其高产量，全面性和日益具有竞争力的成本，基因组测序是一个潜在的第一层基因测试的儿童无法解释的医疗复杂性。医学复杂性（CMC）儿童代表了儿科医疗保健系统中不断增长的人口，具有高资源使用和相关的医疗保健成本。遗传诊断可以告知预后，预期护理，管理和生殖计划。传统的CMC基因检测策略通常是昂贵的，耗时的，最终是不成功的。评价基因组测序作为CMC综合诊断基因检测的分析和临床有效性。在这项前瞻性使用基因组测序并与标准治疗基因检测进行比较的队列研究中，CMC于2017年5月1日至2018年11月30日从加拿大多伦多三级护理儿科医院的结构化复杂护理项目中招募。招募的CMC至少有1种慢性疾病、技术依赖性（儿童每天至少部分时间依赖机械呼吸机，和/或儿童需要长期静脉注射营养物质或药物，和/或儿童预计长期依赖其他基于器械的支持）、多个专科医生参与和大量医疗保健使用。对545名CMC的护理计划进行了审查，发现143名疑似患有未确诊的遗传病。54个家庭符合入选标准并有兴趣参与，49个家庭完成了研究。先证者、相似的受影响的兄弟姐妹和生物学上的父母都有资格进行基因组测序。使用已建立的方法和用于临床基因组注释的生物信息学管道，使用先证者和家族成员的血液来源DNA进行基因组测序。主要研究结果是基因组测序的诊断率（检测结果产生新诊断的CMC比例）。对来自49个CMC家族的138名个体进行了基因组测序（29名男性和20名女性先证者;平均[SD]年龄，7.0 [4.5]岁）。基因组测序检测了所有以前通过常规基因检测确定的基因组变异。共有15名先证者（30.6%; 95%CI 19.5%-44.6%）在基因组测序后接受了新的初步分子遗传学诊断。三个人有新的疾病，另外9个人有超罕见的遗传条件或罕见的遗传条件与非典型特征。至少有11个家庭接受了诊断信息，这些信息具有遗传和生殖咨询以外的临床管理意义。这项研究表明，基因组测序具有很高的分析和临床有效性，即使在广泛的前期研究的背景下，也可以导致CMC的新诊断。这一临床人群可能富含罕见和新型遗传性疾病。基因组测序是CMC潜在的第一级基因检测。这项队列研究评估了基因组测序作为医学复杂性儿童综合诊断基因检测的分析和临床有效性。
What is the diagnostic yield of genome sequencing in children with unexplained medical complexity and prior negative results of genetic testing? In this cohort study that included 138 individuals from 49 families, genome sequencing detected all genomic variation previously identified by conventional genetic testing and resulted in a new diagnosis for 31% of patients. This study suggests that, because of its high yield, comprehensive nature, and increasingly competitive costs, genome sequencing is a potentially first-tier genetic test for children with unexplained medical complexity. Children with medical complexity (CMC) represent a growing population in the pediatric health care system, with high resource use and associated health care costs. A genetic diagnosis can inform prognosis, anticipatory care, management, and reproductive planning. Conventional genetic testing strategies for CMC are often costly, time consuming, and ultimately unsuccessful. To evaluate the analytical and clinical validity of genome sequencing as a comprehensive diagnostic genetic test for CMC. In this cohort study of the prospective use of genome sequencing and comparison with standard-of-care genetic testing, CMC were recruited from May 1, 2017, to November 30, 2018, from a structured complex care program based at a tertiary care pediatric hospital in Toronto, Canada. Recruited CMC had at least 1 chronic condition, technology dependence (child is dependent at least part of each day on mechanical ventilators, and/or child requires prolonged intravenous administration of nutritional substances or drugs, and/or child is expected to have prolonged dependence on other device-based support), multiple subspecialist involvement, and substantial health care use. Review of the care plans for 545 CMC identified 143 suspected of having an undiagnosed genetic condition. Fifty-four families met inclusion criteria and were interested in participating, and 49 completed the study. Probands, similarly affected siblings, and biological parents were eligible for genome sequencing. Genome sequencing was performed using blood-derived DNA from probands and family members using established methods and a bioinformatics pipeline for clinical genome annotation. The primary study outcome was the diagnostic yield of genome sequencing (proportion of CMC for whom the test result yielded a new diagnosis). Genome sequencing was performed for 138 individuals from 49 families of CMC (29 male and 20 female probands; mean [SD] age, 7.0 [4.5] years). Genome sequencing detected all genomic variation previously identified by conventional genetic testing. A total of 15 probands (30.6%; 95% CI 19.5%-44.6%) received a new primary molecular genetic diagnosis after genome sequencing. Three individuals had novel diseases and an additional 9 had either ultrarare genetic conditions or rare genetic conditions with atypical features. At least 11 families received diagnostic information that had clinical management implications beyond genetic and reproductive counseling. This study suggests that genome sequencing has high analytical and clinical validity and can result in new diagnoses in CMC even in the setting of extensive prior investigations. This clinical population may be enriched for ultrarare and novel genetic disorders. Genome sequencing is a potentially first-tier genetic test for CMC. This cohort study evaluates the analytical and clinical validity of genome sequencing as a comprehensive diagnostic genetic test for children with medical complexity.
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影响因子：
17.1
作者：
Cummings BB;Marshall JL;Tukiainen T;Lek M;Donkervoort S;Foley AR;Bolduc V;Waddell LB;Sandaradura SA;O'Grady GL;Estrella E;Reddy HM;Zhao F;Weisburd B;Karczewski KJ;O'Donnell-Luria AH;Birnbaum D;Sarkozy A;Hu Y;Gonorazky H;Claeys K;Joshi H;Bournazos A;Oates EC;Ghaoui R;Davis MR;Laing NG;Topf A;Genotype-Tissue Expression Consortium;Kang PB;Beggs AH;North KN;Straub V;Dowling JJ;Muntoni F;Clarke NF;Cooper ST;Bönnemann CG;MacArthur DG
通讯作者：
MacArthur DG
影响因子：
82.9
作者：
Fresard, Laure;Smail, Craig;Dyment, David
通讯作者：
Dyment, David
影响因子：
5.3
作者：
Clark, Michelle M.;Starke, Zornitza;Kingsmore, Stephen F.
通讯作者：
Kingsmore, Stephen F.
影响因子：
--
作者：
Burke, Wylie
通讯作者：
Burke, Wylie
影响因子：
8
作者：
Cohen, Eyal;Berry, Jay G.;Guttmann, Astrid
通讯作者：
Guttmann, Astrid