PURPOSE: Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing. METHODS: From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses. RESULTS: The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient. CONCLUSION: Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.
PURPOSE: Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing. METHODS: From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses. RESULTS: The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient. CONCLUSION: Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.
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Authors: Margot A Cousin; Emma L Veale; Nikita R Dsouza; Swarnendu Tripathi; Robyn G Holden; Maria Arelin; Geoffrey Beek; Mir Reza Bekheirnia; Jasmin Beygo; Vikas Bhambhani; Martin Bialer; Stefania Bigoni; Cyrus Boelman; Jenny Carmichael; Thomas Courtin; Benjamin Cogne; Ivana Dabaj; Diane Doummar; Laura Fazilleau; Alessandra Ferlini; Ralitza H Gavrilova; John M Graham; Tobias B Haack; Jane Juusola; Sarina G Kant; Saima Kayani; Boris Keren; Petra Ketteler; Chiara Klöckner; Tamara T Koopmann; Teresa M Kruisselbrink; Alma Kuechler; Laëtitia Lambert; Xénia Latypova; Robert Roger Lebel; Magalie S Leduc; Emanuela Leonardi; Andrea M Lewis; Wendy Liew; Keren Machol; Samir Mardini; Kirsty McWalter; Cyril Mignot; Julie McLaughlin; Alessandra Murgia; Vinodh Narayanan; Caroline Nava; Sonja Neuser; Mathilde Nizon; Davide Ognibene; Joohyun Park; Konrad Platzer; Céline Poirsier; Maximilian Radtke; Keri Ramsey; Cassandra K Runke; Maria J Guillen Sacoto; Fernando Scaglia; Marwan Shinawi; Stephanie Spranger; Ee Shien Tan; John Taylor; Anne-Sophie Trentesaux; Filippo Vairo; Rebecca Willaert; Neda Zadeh; Raul Urrutia; Dusica Babovic-Vuksanovic; Michael T Zimmermann; Alistair Mathie; Eric W Klee Journal: Genome Med Date: 2022-06-13 Impact factor: 15.266