First‐Tier Versus Last‐Tier Trio Whole‐Genome Sequencing for the Diagnosis of Pediatric‐Onset Rare Diseases

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.

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Publication Details

Journal
Clinical Genetics
Published
2025-04-24
DOI
https://doi.org/10.1111/cge.14760
Citations
4
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
7.27

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article

First‐Tier Versus Last‐Tier Trio Whole‐Genome Sequencing for the Diagnosis of Pediatric‐Onset Rare Diseases

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4 citations
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Genomics and Rare Diseases
7.27
article

First‐Tier Versus Last‐Tier Trio Whole‐Genome Sequencing for the Diagnosis of Pediatric‐Onset Rare Diseases

Donatella Milani, Maria Rosaria Iascone, Laura Giordano, Luigina Spaccini, Lidia Pezzani, Erica Rosina, Matteo Bellini, Davide Tonduti, Maria Francesca Bedeschi, Camilla Lucca, Alba Pilotta, Daniela Piazzolla, Marco Frigeni, Ezio Bonanomi, Anna Cereda, Cecilia Daolio, Francesca Furlan, Giovanna Mangili, Serena Gasperini, Giovanni Cazzaniga, Ugo Cavallari, Laura Pezzoli, Agnese Scatigno, Lucrezia Goisis, Daniela Marchetti, Elisa Cattaneo, Chiara Mongodi
article en
4 citations

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.

Clinical GeneticsVol. 108(4)
University of Milan (IT), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), Ospedale Papa Giovanni XXIII (IT), Azienda Ospedaliera San Gerardo (IT), Illumina (United Kingdom) (GB), Azienda Ospedaliera Fatebenefratelli e Oftalmico (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University of Milano-Bicocca (IT)
European Commission, Fondazione Telethon
Openalex Percentile: Top 3%
Genomics and Rare Diseases
7.27
DOIOpen Access PDFOpenAlex
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