Diagnostic yield of 1000 trio analyses with exome and genome sequencing in a clinical setting.

Authors

Helena Malmgren, Malin Kvarnung, Peter Gustafsson, Britt-Marie Anderlid, Cecilia Arthur, Jonas Carlsten, Karl De Geer, Emma Ehn, Giedre Grigelioniené, Anna Hammarsjö, Hafdis T Helgadottir, Maritta Hellström-Pigg, Erik Iwarsson, Ekaterina Kuchinskaya, Hillevi Lindelöf, Maria Mannila, Daniel Nilsson, Maria Pettersson, Eva Rudd, Ellika Sahlin, Bianca Tesi, Emma Tham, Håkan Thonberg, Eini Westenius, Johanna Winberg, Max Winerdal, Magnus Nordenskjöld, Maria Johansson-Soller, Valtteri Wirta, Ann Nordgren, Anna Lindstrand, Kristina Lagerstedt-Robinson

Published in

Frontiers in genetics. Volume 16. Pages 1580879. Epub Jun 20, 2025.

Abstract

A trio analysis refers to the strategy of exome or genome sequencing of DNA from a patient, as well as parents, in order to identify the genetic cause of a disorder or syndrome.
During the last 10 years, we have successfully applied exome or genome sequencing and performed trio analysis for 1,000 patients.
Overall, 39% of the patients were diagnosed, with the detection of causative variant(s). The variants were located in 308 different genes. Autosomal dominant de novo variants were detected in 46% of the solved cases. Detection rates were highest in patients with a syndromic neurodevelopmental disorder (46%) and in patients with known consanguinity (59%). Even for patients previously analyzed as singletons, using a pre-defined gene panel, a consecutive trio analysis resulted in the detection of a causative variant in 30%.
A major advantage of trio analysis is the immediate identification of de novo variants as well as confirmation of compound heterozygosity. Additionally, inherited variants from a healthy parent can be dismissed as non-disease causing. The trio strategy enables analysis of a high number of genes-or even the whole genome-simultaneously. The strengths of a trio analysis, in combination with analysis of genome sequence data, allows for the detection of a wide range of genetic aberrations. This enables a high diagnostic yield, even in previously analyzed patients. Our current protocol for trio analysis is based on genome sequencing data, which allows for simultaneous detection of single nucleotide variants, insertion/deletions, structural variants, expanded short tandem repeats, as well as a copy number analysis corresponding to an array-CGH, and analysis regarding SMN1 gene copies.

PMID:
40620702
Bibliographic data and abstract were imported from PubMed on 11 Nov 2025.

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