Lucca Camilla, Rosina Erica, Pezzani Lidia, Piazzolla Daniela, Spaccini Luigina, Scatigno Agnese, Gasperini Serena, Pezzoli Laura, Cereda Anna, Milani Donatella, Cattaneo Elisa, Cavallari Ugo, Frigeni Marco, Marchetti Daniela, Daolio Cecilia, Giordano Laura, Bellini Matteo, Goisis Lucrezia, Mongodi Chiara, Tonduti Davide, Pilotta Alba, Cazzaniga Giovanni, Furlan Francesca, Bedeschi Maria Francesca, Mangili Giovanna, Bonanomi Ezio, Iascone Maria
Laboratory of Medical Genetics, ASST Papa Giovanni XXIII, Bergamo, Italy.
Fondazione IRCCS ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Clin Genet. 2025 Oct;108(4):412-421. doi: 10.1111/cge.14760. Epub 2025 Apr 24.
Despite advances in diagnostics, children with rare genetic disorders still face extended diagnostic odysseys, delaying appropriate clinical management, and placing burdens on families and healthcare resources. Whole-genome sequencing (WGS) offers a more comprehensive interrogation of the genome than other genetic tests, but its use in clinical practice remains limited. This study compared diagnostic rates, turnaround times, and clinical utility of first-tier versus last-tier trio-WGS for patients with suspected genetic pediatric-onset conditions, including 97 critical and 104 non-critical patients. Eighty-five patients (42.3%), including 57 (58.8%) critical and 28 (26.9%) non-critical patients, received a molecular diagnosis. The diagnostic rate was higher for first-tier (57%) than for last-tier (32.8%) trio-WGS. Of 121 causative variants identified, 19.8% would have been missed by whole-exome sequencing. Laboratory processing time was 4 days for all patients. The clinical setting had the greatest impact on time to reporting, averaging 5 days for critical patients versus 74 days for outpatients. WGS results impacted clinical decision-making for 34% of all critical and 14.3% of WGS-positive non-critical patients. This is the first Italian clinical study to demonstrate the diagnostic and clinical utility of a genome-first approach for both critical and non-critical patients with suspected genetic pediatric-onset disorders and feasibility in a public healthcare system.
尽管诊断技术有所进步，但患有罕见遗传疾病的儿童仍面临漫长的诊断过程，这延误了适当的临床治疗，给家庭和医疗资源带来了负担。与其他基因检测相比，全基因组测序（WGS）能对基因组进行更全面的检测，但其在临床实践中的应用仍然有限。本研究比较了一线与末线三联体WGS对疑似遗传性儿童期发病疾病患者的诊断率、周转时间和临床效用，其中包括97例重症患者和104例非重症患者。85例患者（42.3%），包括57例（58.8%）重症患者和28例（26.9%）非重症患者，获得了分子诊断。一线三联体WGS的诊断率（57%）高于末线（32.8%）。在鉴定出的121个致病变异中，19.8%会被全外显子组测序遗漏。所有患者的实验室处理时间均为4天。临床环境对报告时间影响最大，重症患者平均为5天，门诊患者为74天。WGS结果影响了34%的重症患者和14.3%的WGS阳性非重症患者的临床决策。这是意大利第一项临床研究，证明了基因组优先方法对疑似遗传性儿童期发病疾病的重症和非重症患者的诊断和临床效用，以及在公共医疗系统中的可行性。
