Frontiers in Genetics (Jun 2025)

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

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

DOI
https://doi.org/10.3389/fgene.2025.1580879
Journal volume & issue
Vol. 16

Abstract

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IntroductionA 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.MethodsDuring the last 10 years, we have successfully applied exome or genome sequencing and performed trio analysis for 1,000 patients.ResultsOverall, 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%.DiscussionA 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.

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