First‐Tier Versus Last‐Tier Trio Whole‐Genome Sequencing for the Diagnosis of Pediatric‐Onset Rare Diseases
Year: 2025
Type: article
Study design: Observational Study
Abstract: 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.
Source: Clinical Genetics
DOI: 10.1111/cge.14760
Authors: Camilla Lucca, Erica Rosina, Lidia Pezzani, Daniela Piazzolla, Luigina Spaccini, Agnese Scatigno, Serena Gasperini, Laura Pezzoli, Anna Cereda, Donatella Milani, Elisa Cattaneo, Ugo Cavallari, Marco Frigeni, Daniela Marchetti, Cecilia Daolio, Laura Giordano, Matteo Bellini, Lucrezia Goisis, Chiara Mongodi, Davide Tonduti, Alba Pilotta, Giovanni Cazzaniga, Francesca Furlan, Maria Francesca Bedeschi, Giovanna Mangili, Ezio Bonanomi, Maria Iascone
Institutions: Ospedale Papa Giovanni XXIII, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Illumina (United Kingdom), University of Milan, Ospedale dei Bambini Vittore Buzzi, Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, Azienda Ospedaliera Fatebenefratelli e Oftalmico, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, University of Milano-Bicocca
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,980
Funders: European Commission, Fondazione Telethon
Awards: G2819441090, G5855407322
OpenAlex ID: W4409753998