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Background <p>As clinical genetics evolves towards the broader field of clinical genomics, the diagnostic approach to rare diseases is undergoing a paradigm shift. This transformation has significantly impacted rare disease diagnostics, increasingly done through gene panels, whole exome and whole genome sequencing. To advance beyond genomics into precision medicine and encompass the breadth of relevant clinical scenarios, a true systems shift is required that challenges conventional barriers and enables the formation of cross-disciplinary, integrated environments.</p> Methods <p>The Genomic Medicine Center Karolinska Rare Diseases (GMCK-RD) has, for the past 10&#xa0;years, brought together healthcare and academia to enable large-scale genome sequencing in a clinical diagnostics context. Within GMCK-RD, experts from various medical disciplines collaborate closely with clinical geneticists, bioinformaticians, and researchers to integrate genome sequencing into healthcare.</p> Results <p>In total, 15 644 individuals with suspected rare diseases were analyzed using clinical genome sequencing, including pediatric (48%), adult (48%) and fetal (4%) samples. The overall diagnostic yield was 22.6%, providing a diagnosis for 3 538 individuals with variants in 1 570 genes. Moreover, a rare disease analysis tool suite developed and validated <i>in house</i> includes a bioinformatic pipeline allowing for comprehensive data analysis covering a wide range of genetic variants including SNVs, INDELs, repeat expansions, uniparental disomies, balanced and unbalanced structural variants as well as insertions of mobile elements. Results are visualized and interpreted in custom-developed decision support systems functioning as an interpretation portal as well as a knowledge-base to capture the interpretation efforts made in a structured format allowing future secondary use.</p> Conclusions <p>Altogether, GMCK-RD has shifted healthcare in our region towards precision diagnostics. We emphasize the need to transition from traditional clinical genetic diagnostics to a broader clinical genomics approach. Beyond this shift, we advocate integrating genomics with specialized clinical and laboratory medicine, a concept pioneered for inborn errors of metabolism (IEM) with stepwise spread to additional disease groups. In this model, a multidisciplinary unit combines screening, targeted diagnostics, individualized treatment, and long-term patient follow-up. Here we provide a road map and guide for inspiration for centers aiming to implement genome sequencing in rare disease diagnostics.</p>

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The genomic medicine center Karolinska 10-year report on genome sequencing for rare diseases and a strategy for stepwise clinical implementation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月30日

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  • Anna Lindstrand,
  • Kristina Lagerstedt-Robinson,
  • Anders Jemt,
  • Malin Kvarnung,
  • Sofia Ygberg,
  • Sofie Vonlanthen,
  • Mikael Oscarson,
  • Daniel Nilsson,
  • Nicole Lesko,
  • Angelo Salazar Mantero,
  • Britt-Marie Anderlid,
  • Henrik Arnell,
  • Cecilia Arthur,
  • Svetlana Bajalica-Lagercrantz,
  • Michela Barbaro,
  • Peter Bergman,
  • Erik Björck,
  • Oda Blomqvist Picard,
  • Helene Bruhn,
  • Jonas Carlsten,
  • Sandrina P. Correia,
  • Karl De Geer,
  • Angelica M. Delgado Vega,
  • Emma Ehn,
  • Jesper Eisfeldt,
  • Marlene Ek,
  • Ingegerd Elvers,
  • Martin Engvall,
  • Christoph Freyer,
  • Sofia Frisk,
  • Caroline Graff,
  • Giedré Grigelioniené,
  • Peter Gustafsson,
  • Anna Hammarsjö,
  • Hafdis T. Helgadottir,
  • Maritta Hellström Pigg,
  • Olivia J. Henry,
  • Moa Hägglund,
  • Erik Iwarsson,
  • Vincent Janvid,
  • Maria Johansson Soller,
  • Leif Sundin,
  • Ekaterina Kuchinskaya,
  • Anders Kämpe,
  • Anna Leinfelt,
  • Agne Liedén,
  • Hillevi Lindelöf,
  • Anna Lyander,
  • Helena Malmgren,
  • Maria Mannila,
  • Per Marits,
  • Karin Naess,
  • Ramprasad Neethiraj,
  • Karl Nyren,
  • Christoforos Pappas,
  • Martin Paucar,
  • Nadja Pekkola Pacheco,
  • Lucia Peña Perez,
  • Maria Pettersson,
  • Peter Pruisscher,
  • Chiara Rasi,
  • Annick Renevey,
  • Sophia Rössner,
  • Ellika Sahlin,
  • Erik Stenund,
  • Tommy Stödberg,
  • Mikael Sundin,
  • Karl Svärd,
  • Bianca Tesi,
  • Emma Tham,
  • Håkan Thonberg,
  • Virpi Töhönen,
  • Malin Ueberschär,
  • Karin Wallander,
  • Eini Westenius,
  • Johanna Winberg,
  • Nerges Winblad,
  • Josephine Wincent,
  • Malin Winerdal,
  • Anna Wredenberg,
  • Anna Zetterlund,
  • Rolf H. Zetterström,
  • Ingegerd Öfverholm,
  • Ann Nordgren,
  • Henrik Stranneheim,
  • Valtteri Wirta,
  • Anna Wedell

摘要

Background

As clinical genetics evolves towards the broader field of clinical genomics, the diagnostic approach to rare diseases is undergoing a paradigm shift. This transformation has significantly impacted rare disease diagnostics, increasingly done through gene panels, whole exome and whole genome sequencing. To advance beyond genomics into precision medicine and encompass the breadth of relevant clinical scenarios, a true systems shift is required that challenges conventional barriers and enables the formation of cross-disciplinary, integrated environments.

Methods

The Genomic Medicine Center Karolinska Rare Diseases (GMCK-RD) has, for the past 10 years, brought together healthcare and academia to enable large-scale genome sequencing in a clinical diagnostics context. Within GMCK-RD, experts from various medical disciplines collaborate closely with clinical geneticists, bioinformaticians, and researchers to integrate genome sequencing into healthcare.

Results

In total, 15 644 individuals with suspected rare diseases were analyzed using clinical genome sequencing, including pediatric (48%), adult (48%) and fetal (4%) samples. The overall diagnostic yield was 22.6%, providing a diagnosis for 3 538 individuals with variants in 1 570 genes. Moreover, a rare disease analysis tool suite developed and validated in house includes a bioinformatic pipeline allowing for comprehensive data analysis covering a wide range of genetic variants including SNVs, INDELs, repeat expansions, uniparental disomies, balanced and unbalanced structural variants as well as insertions of mobile elements. Results are visualized and interpreted in custom-developed decision support systems functioning as an interpretation portal as well as a knowledge-base to capture the interpretation efforts made in a structured format allowing future secondary use.

Conclusions

Altogether, GMCK-RD has shifted healthcare in our region towards precision diagnostics. We emphasize the need to transition from traditional clinical genetic diagnostics to a broader clinical genomics approach. Beyond this shift, we advocate integrating genomics with specialized clinical and laboratory medicine, a concept pioneered for inborn errors of metabolism (IEM) with stepwise spread to additional disease groups. In this model, a multidisciplinary unit combines screening, targeted diagnostics, individualized treatment, and long-term patient follow-up. Here we provide a road map and guide for inspiration for centers aiming to implement genome sequencing in rare disease diagnostics.