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. 2024 Jan;12(1):e2316.
doi: 10.1002/mgg3.2316. Epub 2023 Dec 2.

Comparison of first-tier whole-exome sequencing with a multi-step traditional approach for diagnosing paediatric outpatients: An Italian prospective study

Erica Rosina  1 , Lidia Pezzani  2 , Erika Apuril  1 , Laura Pezzoli  1 , Daniela Marchetti  1 , Matteo Bellini  1 , Camilla Lucca  1 , Camilla Meossi  3 , Marta Massimello  4 , Milena Mariani  5 , Agnese Scatigno  2 , Elisa Cattaneo  6 , Lorenzo Colombo  7 , Silvia Maitz  8 , Anna Cereda  2 , Donatella Milani  3 , Luigina Spaccini  6 , Maria Francesca Bedeschi  9 , Angelo Selicorni  5 , Maria Iascone  1
Affiliations

Comparison of first-tier whole-exome sequencing with a multi-step traditional approach for diagnosing paediatric outpatients: An Italian prospective study

Erica Rosina et al. Mol Genet Genomic Med. 2024 Jan.

Abstract

Background: The recent guidelines suggest the use of genome-wide analyses, such as whole exome sequencing (WES), at the beginning of the diagnostic approach for cases with suspected genetic conditions. However, in many realities it still provides for the execution of a multi-step pathway, thus requiring several genetic tests to end the so-called 'diagnostic odyssey'.

Methods: We reported the results of GENE Project (Genomic analysis Evaluation NEtwork): a multicentre prospective cohort study on 125 paediatric outpatients with a suspected genetic disease in which we performed first-tier trio-WES, including exome-based copy number variation analysis, in parallel to a 'traditional approach' of two/three sequential genetic tests.

Results: First-tier trio-WES detected a conclusive diagnosis in 41.6% of patients, way above what was found with routine genetic testing (25%), with a time-to-result of about 50 days. Notably, the study showed that 44% of WES-reached diagnoses would be missed with the traditional approach. The diagnostic rate (DR) of the two approaches varied in relation to the phenotypic class of referral and to the proportion of cases with a defined diagnostic suspect, proving the major difference for neurodevelopmental disorders. Moreover, trio-WES analysis detected variants in candidate genes of unknown significance (EPHA4, DTNA, SYNCRIP, NCOR1, TFDP1, SPRED3, EDA2R, PHF12, PPP1R12A, WDR91, CDC42BPG, CSNK1D, EIF3H, TMEM63B, RIPPLY3) in 19.4% of undiagnosed cases.

Conclusion: Our findings represent real-practice evidence of how first-tier genome-wide sequencing tests significantly improve the DR for paediatric outpatients with a suspected underlying genetic aetiology, thereby allowing a time-saving setting of the correct management, follow-up and family planning.

Keywords: delayed diagnosis; genetic testing; paediatric patients; traditional approach; whole exome sequencing.

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Conflict of interest statement

The authors declare no conflict/competing interests.

Figures

FIGURE 1
FIGURE 1
Project GENE method and results. A flowchart of the project is shown (a), with the percentage and type of diagnoses and uncertain outcomes identified with first‐tier trio‐WES (b) and traditional approach (c). A comparison in terms of diagnostic rates between the two approaches is represented in (d). CMA, chromosomal microarray; GUS, genes of unknown significance; VUS, variants of unknown significance.
See this image and copyright information in PMC

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