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

Helena Malmgren^1,2Malin Kvarnung^1,2Peter Gustafsson^1,2Britt-Marie Anderlid^1,2Cecilia Arthur^1,2Jonas Carlsten^1,2Karl De Geer^1,2Emma Ehn^1,2Giedré Grigelioniené^1,2Anna Hammarsjö^1,2Hafdis T Helgadóttir^1,2Maritta Hellström-Pigg^1,2Erik Iwarsson^1,2Ekaterina Kuchinskaya¹Hillevi Lindelöf^1,2Maria Mannila^1,2Daniel Nilsson^1,2,3Maria Pettersson^1,2Eva Rudd^1,2Ellika Sahlin^1,2Bianca Tesi^1,2Emma Tham^1,2Håkan Thonberg^1,2Eini Westenius^1,2Johanna Winberg^1,2Max Winerdal¹Magnus Nordenskjöld^1,2Maria Johansson-Soller^1,2Valtteri Wirta^1,2,3Ann Nordgren^1,2Anna Lindstrnad^1,2Kristina Lagerstedt-Robinson^1,2*

• ¹Karolinska University Hospital, Solna, Stockholm, Sweden
• ²Karolinska Institutet (KI), Solna, Stockholm, Sweden
• ³Science for Life Laboratory (SciLifeLab), Solna, Stockholm, Sweden

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 1000 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.