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. 2025 Jun 20:16:1580879.
doi: 10.3389/fgene.2025.1580879. eCollection 2025.

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

Helena Malmgren  1   2 , Malin Kvarnung  1   2 , Peter Gustafsson  1   2 , Britt-Marie Anderlid  1   2 , Cecilia Arthur  1   2 , Jonas Carlsten  1   2 , Karl De Geer  1   2 , Emma Ehn  1   2 , Giedre Grigelioniené  1   2 , Anna Hammarsjö  1   2 , Hafdis T Helgadottir  1   2 , Maritta Hellström-Pigg  1   2 , Erik Iwarsson  1   2 , Ekaterina Kuchinskaya  1   2 , Hillevi Lindelöf  1   2 , Maria Mannila  1   2 , Daniel Nilsson  1   3 , Maria Pettersson  1   2 , Eva Rudd  1   2 , Ellika Sahlin  1   2 , Bianca Tesi  1   2 , Emma Tham  1   2 , Håkan Thonberg  1   2 , Eini Westenius  1   2 , Johanna Winberg  1   2 , Max Winerdal  1   2 , Magnus Nordenskjöld  1   2 , Maria Johansson-Soller  1   2 , Valtteri Wirta  1   4 , Ann Nordgren  1   2 , Anna Lindstrand  1   2 , Kristina Lagerstedt-Robinson  1   2
Affiliations

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

Helena Malmgren et al. Front Genet. .

Abstract

Introduction: 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.

Methods: During the last 10 years, we have successfully applied exome or genome sequencing and performed trio analysis for 1,000 patients.

Results: 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%.

Discussion: 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.

Keywords: NDD; de novo; exome; genome; syndrome; trio analysis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Distribution of the patient subgroups in the analyzed cohort based upon clinical phenotype. The largest cohort was the patients with syndrome including NDD (49%) followed by patients with a syndrome without NDD (37%) and patients with only NDD (8%). Finally, a small proportion of the patients were fetuses. NDD, neuro developmental disorder.
FIGURE 2
FIGURE 2
Trio based diagnostics performed by ES (black bars) and GS (grey bars) from May 2012-January 2023. Timeline showing integration of new components to the workflow (illustrated by arrows). ES, Exome sequencing; GS, Genome Sequencing; SNVs and INDELs, Single nucleotide variants and smaller insertions and/or deletions; SVs, Structural variants; STRs, Short tandem repeats; SMN, Copy number identification of SMN1 and SMN2 genes; MEIs, Mobile element insertions.
FIGURE 3
FIGURE 3
Illustration and distribution of the different inheritance patterns among solved cases in the study. AD, Autosomal dominant; AR, Autosomal recessive; XL, X-linked.
FIGURE 4
FIGURE 4
Flowchart describing the outcome of trio analyses performed between January 2018- January 2023.
See this image and copyright information in PMC

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