Abstract
Rare and undiagnosed diseases pose diagnostic challenges due to phenotypic and genetic heterogeneity and the limitations of conventional molecular testing. As part of the RareBoost project, we implemented an integrated, stepwise genomic strategy in a cohort of 134 patients from 120 families with previously inconclusive genetic testing. Our strategy combined systematic exome sequencing with subsequent genome sequencing when indicated, followed by targeted RNA-sequencing, and complemented with comprehensive phenotyping and follow-up segregation analysis. Definitive molecular diagnoses (pathogenic/likely pathogenic variants) were achieved in 25.0% of families, and an additional 25.8% harbored clinically relevant variants of uncertain significance with phenotypic correlation. This approach identified non-coding and structural variants while resolving cases through systematic reanalysis of previously negative data. Collectively, our findings demonstrate that integrated genomic and transcriptomic analyses with reanalysis of existing data enhance diagnostic yield in complex rare disease cohorts and provide a scalable framework for implementing genomic medicine in clinical practice.
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Data availability
The datasets generated and analyzed during this study are available from the corresponding author upon reasonable request, in accordance with ethical approvals and applicable data protection regulations
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Acknowledgements
The authors thank the Izmir Biomedicine and Genome Center Biobank and Biomolecular Resources Platform (IBG-Biobank) for the use of its facilities and services, as well as for collecting, processing, storing, and making available the biological samples and data used in this study. This work was supported by the RareBoost Project, funded by the European Union’s Horizon 2020 research and innovation programme (Grant No. 952346; https://rareboost.ibg.edu.tr/), and by the ERDERA Project (Grant No. 101156595). We also gratefully acknowledge TÜSEB for enabling genome sequencing analyses for our patients. We sincerely thank all clinicians, researchers, and members of the Rare and Undiagnosed Disease Platform (RUDiP) who contributed to the Rare and Undiagnosed Patients Advisory Board meetings, as well as the patients and their families for their invaluable participation. We further acknowledge Gennext, Genomics and More for their genomic and transcriptomic services. Finally, we thank Prof. Dr. Sibel Ugur Iseri for the critical reading of the manuscript.
Funding
We would like to acknowledge the support of the RareBoost project, funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 952346. This initiative has substantially enhanced the research and innovation capacity in the field of rare diseases at the Izmir Biomedicine and Genome Center and across the broader region of Türkiye, fostering progress in diagnostics and further studies of rare and undiagnosed conditions
Author information
Authors and Affiliations
Rare and Undiagnosed Diseases Group, Izmir Biomedicine and Genome Center, Izmir, Türkiye
Ayca Yigit, Mert Pekerbas, Baris Salman, Kutay Bulut, Emre Ozzeybek, Mehmet Mert Topaloglu, Burcu Akman, Ravza Nur Yildirim, Sinem Aktug, Tugce Batur, Ahmet Okay Caglayan, Aliye Kubra Unal, Inci Yaprak, Evin Iscan, Miray Sevinin, Mehmet Baysan, Yavuz Oktay & Ugur Ozbek
Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Türkiye
Ayca Yigit, Kutay Bulut, Emre Ozzeybek & Beste Ozkalay
Institute of Graduate Studies in Health Sciences, Istanbul University, Istanbul, Türkiye
Baris Salman
Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Türkiye
Baris Salman
Ege University, Institute of Health Sciences, Izmir, Türkiye
Mehmet Mert Topaloglu & Caglar Celebi
Biobank and Biomolecular Rekiye
Beste Ozkalay, Caglar Celebi, Nese Atabey & Sanem Tercan Avci
Department of Pediatric Neurology, Faculty of Medicine, Dokuz Eylül University, Izmir, Türkiye
Ayse Ipek Polat, Ayse Semra Hiz, Uluc Yis, Huseyin Bahadır Senol, Mustafa Halk, Elif Naz Kadem & Dilek Sonmezoglu
Department of Medical Genetics, Faculty of Medicine, Ege University, Izmir, Türkiye
Asude Durmaz, Ayca Aykut & Haluk Akin
Department of Pediatric Neurology, Izmir Bayrakli City Hospital, Izmir, Türkiye
Pinar Gencpinar, Safa Mete Dagdas & Mehmet Semiz
Department of Pediatric Genetics, Faculty of Medicine, Dokuz Eylül University, Izmir, Türkiye
Ozlem Giray & Semra Gursoy
Department of Pediatric Metabolism, Faculty of Medicine, Harran University, Sanliurfa, Türkiye
Seda Gunes
Department of Medical Genetics, Faculty of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Türkiye
Ozlem Akgun Dogan
Department of Pediatric Neurology, Faculty of Medicine, Kocaeli University, Kocaeli, Türkiye
Bulent Kara
Department of Pediatric Genetics, Faculty of Medicine, Ege University, Izmir, Türkiye
Esra Isik & Tahir Atik
Department of Pediatric Metabolism, Faculty of Medicine, Dokuz Eylül University, Izmir, Türkiye
Merve Bilen, Nur Arslan & Pelin Teke
Department of Pediatric Metabolism, Faculty of Medicine, Fırat University, Elazıg, Türkiye
Abdurrahman Akgun
Department of Pediatric Hematology, Faculty of Medicine, Inonu University, Malatya, Türkiye
Arzu Akyay
Department of Pediatric Rheumatology, Faculty of Medicine, Dokuz Eylül University, Izmir, Türkiye
Aslihan Uzun
Department of Medical Genetics, Faculty of Medicine, Aydın Adnan Menderes University, Aydın, Türkiye
Aydan Mengubas Erbas
Department of Medical Genetics, Izmir Bayrakli City Hospital, Izmir, Türkiye
Berk Ozyilmaz
Department of Medical Genetics, Faculty of Medicine, Canakkale Onsekiz Mart University, Canakkale, Türkiye
Fatma Silan
Department of Medical Genetics, Faculty of Medicine, Pamukkale University, Denizli, Türkiye
Gokhan Ozan Cetin
Department of Pediatric Metabolism, Faculty of Medicine, Gaziantep University, Gaziantep, Türkiye
Ilknur Surucu Kara
Department of Pediatric Endocrinology, Faculty of Medicine, Dokuz Eylül University, Izmir, Türkiye
Korcan Demir
Department of Pediatric Metabolism, Faculty of Medicine, Kocaeli University, Kocaeli, Türkiye
Ozlem Unal Uzun
Department of Pediatric Metabolism, Bursa Yüksek İhtisas Training and Research Hospital, Bursa, Türkiye
Sevil Yildiz
Department of Neurology, Faculty of Medicine, Dokuz Eylül University, Izmir, Türkiye
Tolga Polat
Department of Pediatric Rheumatology, Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Türkiye
Sezgin Sahin
Department of Pediatric Genetics, Faculty of Medicine, Akdeniz University, Antalya, Türkiye
Ercan Mihci
Department of Pediatric Metabolism, Eskisehir Osmangazi University, Eskisehir, Türkiye
Gonca Kilic Yildirim
Department of Pediatric Metabolism, Van Training and Research Hospital, Van, Türkiye
Fehime Erdem
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- Ayca YigitView author publications
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- Mert PekerbasView author publications
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- Baris SalmanView author publications
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- Kutay BulutView author publications
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- Emre OzzeybekView author publications
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- Mehmet Mert TopalogluView author publications
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- Burcu AkmanView author publications
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- Ravza Nur YildirimView author publications
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- Sinem AktugView author publications
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- Tugce BaturView author publications
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Consortia
Rare and Undiagnosed Diseases Advisory Board Consortium
- Ahmet Okay Caglayan
- , Aliye Kubra Unal
- , Inci Yaprak
- , Beste Ozkalay
- , Caglar Celebi
- , Evin Iscan
- , Miray Sevinin
- , Mehmet Baysan
- , Nese Atabey
- , Sanem Tercan Avci
- , Yavuz Oktay
- , Ayse Ipek Polat
- , Ayse Semra Hiz
- , Uluc Yis
- , Huseyin Bahadır Senol
- , Mustafa Halk
- , Elif Naz Kadem
- , Dilek Sonmezoglu
- , Asude Durmaz
- , Ayca Aykut
- , Haluk Akin
- , Pinar Gencpinar
- , Safa Mete Dagdas
- , Mehmet Semiz
- , Ozlem Giray
- , Semra Gursoy
- , Seda Gunes
- , Ozlem Akgun Dogan
- , Bulent Kara
- , Esra Isik
- , Tahir Atik
- , Merve Bilen
- , Nur Arslan
- , Pelin Teke
- , Abdurrahman Akgun
- , Arzu Akyay
- , Aslihan Uzun
- , Aydan Mengubas Erbas
- , Berk Ozyilmaz
- , Fatma Silan
- , Gokhan Ozan Cetin
- , Ilknur Surucu Kara
- , Korcan Demir
- , Ozlem Unal Uzun
- , Sevil Yildiz
- , Tolga Polat
- , Sezgin Sahin
- , Ercan Mihci
- , Gonca Kilic Yildirim
- , Fehime Erdem
- & Ugur Ozbek
Contributions
Conceptualization: AY, MP, KB, BS, EO, MMT, BA, and UO. Data curation: AY, MP, KB, BS, EO, MMT, and BA. Formal analysis: AY, MP, MMT, EO, BS, and RNY. Funding acquisition: UO. Investigation: AY, MP, MMT, BS, EO, BA, and RNY. Methodology: AY, MP, MMT, BS, EO, and RNY. Project administration: UO and SA. Resources: UO, Rare and Undiagnosed Diseases Advisory Board Consortium. Software: EO, BS, and MP. Supervision: UO and BA. Validation: AY, SA, and TB. Visualization: AY, MP, EO, BS, and KB. Writing—original draft: AY, MP, MMT, and BS. Writing—review and editing: all authors. All authors read and approved the final manuscript.
Ethics declarations
Competing interests
The authors declare no competing interests
Ethical approval and consent to participate
The RareBoost Project was approved by the IBG Non-interventional Research Ethics Board, with protocol number 2023-039, in compliance with the principles of the Declaration of Helsinki. All families have been informed and have agreed to this publication of history and data. No images and videos of the patient have been included in this work
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Cite this article
Yigit, A., Pekerbas, M., Salman, B. et al. Integrative and systematic genomic approaches to improve diagnosis in rare and undiagnosed diseases: results from the RareBoost project.
Eur J Hum Genet (2026). https://doi.org/10.1038/s41431-026-02177-9
Received:26 January 2026
Accepted:23 June 2026
Published:09 July 2026
Version of record:09 July 2026
DOI
:https://doi.org/10.1038/s41431-026-02177-9
