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

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

JOURNAL=Frontiers in Genetics

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2025.1580879

DOI=10.3389/fgene.2025.1580879

ISSN=1664-8021

ABSTRACT=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.